IMIDAZO[1,2-a]PYRIDINE COMPOUNDS

ABSTRACT

Imidazo[1,2-a]pyridines are disclosed. Compounds of the invention are useful therapeutic agents and their inclusion in pharmaceutical formulations and use in methods of treatment are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119(e) to U.S.Provisional Patent Application No. 61/054,432 filed on May 19, 2008 andU.S. Provisional Patent Application No. 61/054,437 filed on May 19,2008, the disclosures of which are incorporated herein by reference intheir entirety for all purposes.

FIELD OF THE INVENTION

The invention relates to imidazo[1,2-a]pyridines and the use of suchcompounds in treating and preventing various conditions, includinganxiety.

BACKGROUND OF THE INVENTION

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitterwithin the central nervous system (CNS). GABA_(A) receptors are ligandgated ion channels that are made up from a large range of differentsubunits (α1-6, β-3, γ1-3, δ, ε, π, and θ). Each receptor complexcomprises five subunits, with the dominant in vivo combination thoughtto be 2α2β1γ. Several therapeutic agents exert their effects bymodulating this receptor complex, but adverse effects, particularlysedation, are common and, in part, a consequence of poor subunitselectivity. The existence of a large number of different GABA-Areceptors resulting from subunit heterogeneity indicates that there areexcellent prospects for developing more selective drugs for thetreatment of CNS disorders with reduced side effects. To date, themajority of the ligands that have been identified bind to α subunitsthat are sensitive to classical benzodiazepines, namely α1, α2, α3 andα5. Without exception, these ligands bind allosterically to thereceptor, rather than by occupying the orthosteric (GABA) site and canexert a range of pharmacological activities including agonists,antagonists, partial agonists, and inverse agonists.

Agents that bind or interact with the modulatory sites on the GABA_(A)receptor complex, such as the benzodiazepine receptor, can have eitheran enhancing effect on the action of GABA, i.e. a positive modulatoryeffect of the receptor (agonists, partial agonists), an attenuatingeffect on the action of GABA, i.e. negative modulation of the receptor(inverse agonists, partial inverse agonists), or they can block theeffect of both agonists and inverse agonists by competitive block(antagonists or ligands without intrinsic activity).

SUMMARY OF THE INVENTION

In various embodiments, the present invention provides a compound havinga structure according to Formula I:

In Formula I, R¹, R², R³ and R⁴ are each independently selected from H,D, halogen, hydroxyl, dialkylamino, cyano, sulfonamide, acyl,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl. Thesymbols R⁵ and R⁶ represent members independently selected from H; F;hydroxyl; substituted or unsubstituted alkoxy and lower alkyl. Q isselected from:

Ring system A is an optionally substituted 4, 5, 6 or 7 membermonocyclic or 8, 9, 10, 11 or 12 member bicyclic ring comprising 0, 1,2, 3 or 4 heteroatoms independently selected from N, O and S. The symbolX represents O, S or NR⁷. R⁷ is selected from H; substituted orunsubstituted alkyl; substituted or unsubstituted heteroalkyl;substituted or unsubstituted cycloalkyl; substituted or unsubstitutedheterocycloalkyl; substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl. Y is a member selected from a bond,(CR⁸R⁹)_(n), O, S, NR¹⁰R¹¹, S(O), S(O)₂, S(O)_(p)NR¹⁰R¹¹,(CR⁸R⁹)_(n)G(CR⁸R⁹)_(m). G is a member selected from a bond and O. Theindeces m and n are independently selected integers from 0 to 4. EachR⁸, R⁹ and R¹⁰ are independently selected from H, D, substituted orunsubstituted alkyl, acyl, SO₂R^(8a), OR^(8a), COOR^(8a), andCONR^(8a)R^(8b). R^(8a) and R^(8b) are independently selected from H, D,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl. A member selected from R⁸ andR⁹, R^(8a) and R^(8b) and a combination thereof are optionally joined ina ring. The index n is the integer 0, 1, 2, 3 or 4. R⁸, R⁹ and R¹⁰ areindependently H, D, substituted or unsubstituted alkyl, acyl, SO₂R^(8a),OR^(8a), COOR^(8a), or CONR^(8a)R^(8b). The symbols R^(8a) and R^(8b)independently represent H, D, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl or substituted or unsubstituted heteroaryl. R¹¹ isa bond or NH. Z is CR¹² or N. R¹² is H; substituted or unsubstitutedalkyl; substituted or unsubstituted heteroalkyl; substituted orunsubstituted cycloalkyl; substituted or unsubstituted heterocycloalkyl;substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl. The compounds of the present invention are capable ofmodulating the benzodiazepine receptor. In various embodiments, thecompounds of the present invention are capable of modulating GABA_(A)receptor subtypes. In some embodiments, the compounds of the presentinvention are capable of selectively modulating GABA_(A) receptorsubtypes.

In various embodiments, the invention also provides salts of thecompounds of Formula I, including pharmaceutically acceptable salts,pharmaceutical formulations including the salts and methods of using thesalts and pharmaceutical formulations including the salts to treat,ameliorate and prevent various diseases, syndromes and conditions.

In various embodiments, the present invention also providespharmaceutical compositions comprising a pharmaceutically acceptablecarrier and any compound described herein.

The present invention also provides methods for treating or preventing adisease or condition. Exemplary conditions include, but are not limitedto anxiety disorders, psychiatric disorders, convulsive disorders,aggressive behavior, muscle spasms or tension, depressive or bipolardisorders, cognitive disorders, sleeping disorders, neurodegenerativeeye diseases, neurodegeneration, pain, schizophrenia, emesis, and eatingdisorders, comprising administering to a patient a therapeuticallyeffective amount of any compound described herein.

Other embodiments, objects and advantages of the present invention areset forth in the detailed description that follows

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they optionally encompasssubstituents resulting from writing the structure from right to left,e.g., —CH₂O— optionally also recites —OCH₂—.

The symbol “H” represents hydrogen and, optionally, deuterium andtritium. When H is a component of a chemical formula it representsdeuterium and tritium as well. Replacement of hydrogen with its heavierisotopes is well within the abililities of those of skill in the art.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which can be fullysaturated, mono- or polyunsaturated and can include mono-, di- andmultivalent radicals, having the number of carbon atoms designated (i.e.C₁-C₁₀ means one to ten carbons). Examples of saturated hydrocarbonradicals include, but are not limited to, groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,(cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. Examples of unsaturated alkyl groups include, but are not limitedto, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butyryl, and the higher homologs and isomers. Alkyl groups that arelimited to hydrocarbon groups are termed “homoalkyl”. “Lower alkyl”refers to alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, s- and t-butyl and the like.

The term “alkenyl” by itself or as part of another substituent is usedin its conventional sense, and refers to a radical derived from analkene, as exemplified, but not limited by, substituted or unsubstitutedvinyl and substituted or unsubstituted propenyl. Typically, an alkenylgroup will have from 1 to 24 carbon atoms, with those groups having from1 to 10 carbon atoms being generally preferred.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified, but notlimited, by —CH₂CH₂CH₂CH₂—, and further includes those groups describedbelow as “heteroalkylene.” Typically, an alkyl (or alkylene) group willhave from 1 to 24 carbon atoms, with those groups having 10 or fewercarbon atoms being preferred in the present invention. A “loweralkylene” is a short chain group, generally having, for example, 1, 2,3, 4, 5, 6, 7 or 8 carbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, a nitrogenatom, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and at least one heteroatom selected fromthe group consisting of O, N, Si, P, B, and S, and wherein the nitrogen,phosphorus and sulfur atoms can optionally be oxidized and the nitrogenheteroatom can optionally be quaternized. The heteroatom(s) O, N and Sand Si can be placed at any interior position of the heteroalkyl groupor at the position at which the alkyl group is attached to the remainderof the molecule. Examples of heteroalkyl groups include, but are notlimited to, —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. Up to two heteroatomscan be consecutive, such as, for example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃. Similarly, the term “heteroalkylene” by itself or aspart of another substituent means a divalent radical derived fromheteroalkyl, as exemplified, but not limited by, —CH₂—CH₂—S—CH₂—CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can alsooccupy either or both of the chain termini (e.g., alkyleneoxy,alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Stillfurther, for alkylene and heteroalkylene linking groups, no orientationof the linking group is implied by the direction in which the formula ofthe linking group is written. For example, the formula —CO₂R′—represents both —C(O)OR′ and —OC(O)R′.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. A “cycloalkyl”or “heterocycloalkyl” substituent can be attached to the remainder ofthe molecule directly or through a linker, wherein the linker ispreferably alkylene. An cycloalkyl or heterocycloalkyl group can beattached to the remainder of the molecule through a linkage to an atomthat forms part of the cycloalkyl or heterocycloalkyl ring or through alinkage to a substituent of the cycloalkyl or heterocycloalkyl ring.Examples of cycloalkyl include, but are not limited to, cyclopentyl,cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.Examples of heterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The term “halo” or “halogen,” by itself or as part of anothersubstituent, means, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl, polyhaloalkyl and perhaloalkyl. Forexample, the term “halo(C₁-C₄)alkyl” is mean to include, but not belimited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, substituent that can be a single ring or multiple rings (e.g.,1, 2 or 3 rings), which are fused together, linked covalently or acombination thereof. The term “heteroaryl” refers to aryl groups thatcontaining 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O, S, Si andB, wherein the nitrogen and sulfur atoms are optionally oxidized, andthe nitrogen atom(s) are optionally quaternized. A heteroaryl group canbe attached to the remainder of the molecule through a heteroatom. Anaryl or heteroaryl group can be attached to the remainder of themolecule through a linkage to an atom that forms part of the aryl orheteroaryl ring or through a linkage to a substituent of the aryl orheteroaryl ring. Non-limiting examples of aryl and heteroaryl groupsinclude phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl,pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl,purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituentsfor each of the above noted aryl and heteroaryl ring systems areselected from the group of acceptable substituents described below.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) optionally includes both aryl andheteroaryl rings as defined above. Thus, the term “arylalkyl” optionallyincludes those radicals in which an aryl group is attached to an alkylgroup (e.g., benzyl, phenethyl, pyridylmethyl and the like) includingthose alkyl groups in which a carbon atom (e.g., a methylene group) hasbeen replaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

“Ring” or “ring system” as used herein means a substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. A ring can include fused ring moieties. The number of atomsin a ring is typically defined by the number of members in the ring. Forexample, a “5- to 8-member ring” means there are 5, 6, 7 or 8 atoms inthe encircling arrangement. The ring optionally includes at least oneheteroatom. Thus, the term “5- to 8-member ring” includesheterocycloalkyl and heteroaryl systems, for example, pyridinyl andpiperidinyl. The term “ring” further includes a ring system comprisingmore than one “ring”, wherein each “ring” is independently defined asabove.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,”“arylalkyl,” “heteroaryl,” “heteroarylalkyl”) includes both substitutedand unsubstituted forms of the indicated radical. Exemplary substituentsfor each type of radical are provided below. It will be understood that“substitution”, “substituted” or “substituted with” includes theimplicit proviso that such substitution is in accordance with permittedvalence of the substituted atom and the substituent, and that thesubstitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) are generically referred to as “alkyl groupsubstituents,” and they can be one or more of a variety of groupsselected from, but not limited to: substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocycloalkyl, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen,—SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′“)=NR”,—NR—C(NR′R″)=NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and—NO₂ in a number ranging from zero to (2 m′+1), where m′ is the totalnumber of carbon atoms in such radical. R′, R″, R′″ and R″″ eachpreferably independently refer to hydrogen, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, e.g., aryl substitutedwith 1-3 halogens, substituted or unsubstituted alkyl, alkoxy orthioalkoxy groups, or arylalkyl groups. When a compound of the inventionincludes more than one R group, for example, each of the R groups isindependently selected as are each R′, R″, R′″ and R″″ groups when morethan one of these groups is present. When R′ and R″ are attached to thesame nitrogen atom, they can be combined with the nitrogen atom to forma 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant to include,but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the abovediscussion of substituents, one of skill in the art will understand thatthe term “alkyl” is meant to include groups including carbon atoms boundto groups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and—CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and thelike).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are generically referredto as “aryl group substituents.” The substituents are selected from, forexample: substituted or unsubstituted alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycloalkyl, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′“)=NR″″,—NR—C(NR′R″)=NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and—NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl,in a number ranging from zero to the total number of open valences onthe aromatic ring system; and where R′, R″, R′″ and R″″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl. When acompound of the invention includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R′″and R″″ groups when more than one of these groups is present.

The term “perfluoro lower alkyl” refers to a lower alkyl fluorocarbon inwhich all hydrogen atoms directly attached to the carbon atoms arereplaced by fluorine.

The term “lower alkyl sulfonamido” refers to a residue of formula (loweralkyl-SO₂NR—), wherein R is hydrogen or a C₁ to C₂₀ hydrocarbon, and thepoint of attachment is through N.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringcan optionally be replaced with a substituent of the formula-T-C(O)—(CRR′)_(q)—U—, wherein T and U are independently —NR—, —O—,—CRR′— or a single bond, and q is an integer of from 0 to 3.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring can optionally be replaced with a substituent of theformula -A-(CH₂)_(r)—B—, wherein A and B are independently —CRR′—, —O—,—NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is aninteger of from 1 to 4. One of the single bonds of the new ring soformed can optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring canoptionally be replaced with a substituent of the formula—(CRR′)_(s)—X—(CR″R′″)_(d)—, where s and d are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituents R, R′, R″ and R′″ are preferably independently selectedfrom hydrogen or substituted or unsubstituted (C₁-C₆)alkyl.

As used herein, the term “acyl” describes a substituent containing acarbonyl residue, C(O)R. Exemplary species for R include H, D, halogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, and substituted orunsubstituted heterocycloalkyl.

As used herein, the term “fused ring system” means at least two rings,wherein each ring has at least 2 atoms in common with another ring.“Fused ring systems” can include aromatic as well as nonaromatic rings.Examples of “fused ring systems” are naphthalenes, indoles, quinolines,chromenes and the like.

As used herein, the term “heteroatom” includes oxygen (O), nitrogen (N),sulfur (S) and silicon (Si), boron (B) and phosphorus (P).

The symbol “R” is a general abbreviation that represents a substituentgroup, e.g., one that is selected from substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, andsubstituted or unsubstituted heterocycloalkyl groups. Superscriptedvariants, such as R′, R″, and the like, are used similarly.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. Certain compoundsof the present invention can exist in multiple crystalline or amorphousforms (“polymorphs”). In general, all physical forms are of use in themethods contemplated by the present invention and are intended to bewithin the scope of the present invention. “Compound or apharmaceutically acceptable salt, hydrate, polymorph or solvate of acompound” intends the inclusive meaning of “or”, in that materialsmeeting more than one of the stated criteria are included, e.g., amaterial that is both a salt and a solvate is encompassed.

Many of the compounds described herein contain one or more asymmetriccenters and can thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that can be defined, in terms of absolutestereochemistry, as (R)— or (S)—. The present invention is meant toinclude all such possible isomers, as well as their racemic andoptically pure forms. Optically active (R)— and (S)— isomers can beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms are alsointended to be included.

The graphic representations of racemic, ambiscalemic and scalemic orenantiomerically pure compounds used herein are taken from Maehr, J.Chem. Ed., 62, 114-120 (1985): Solid and broken wedges are used todenote the absolute configuration of a chiral element; solid and brokenbold lines are geometric descriptors indicating the relativeconfiguration shown but denoting racemic character; and wedge outlinesand dotted or broken lines denote enantiomerically pure compounds ofindeterminate absolute configuration. Thus, the formula X encompassesboth of the pure enantiomers of that pair:

The compounds falling within the foregoing parent genus and theirsubgenera can be useful as inhibitors of the neurotransmitterGamma-aminobutyric acid (GABA).

It will be recognized that the compounds of this invention can exist inradiolabeled form, i.e., the compounds can contain one or more atomscontaining an atomic mass or mass number different from the atomic massor mass number usually found in nature. Radioisotopes of hydrogen,carbon, phosphorous, fluorine, chlorine and iodine include ³H, D, ¹⁴C,³⁵S, ¹⁸F, ³⁶Cl and ¹²⁵I, respectively. Compounds that contain thoseradioisotopes and/or other radioisotopes of other atoms are within thescope of this invention. Tritiated, i.e., ³H, D, and carbon-14, i.e.,¹⁴C, radioisotopes are particularly preferred for their ease inpreparation and detectability. Radiolabeled compounds of this inventioncan generally be prepared by methods well known to those skilled in theart. Conveniently, such radiolabeled compounds can be prepared bycarrying out the procedures disclosed in the Examples by substituting areadily available radiolabeled reagent for a non-radiolabeled reagent.Because of the high affinity for the GABA receptor, radiolabeledcompounds of the invention are useful for GABA assays.

The phrase “therapeutically effective amount” as used herein means thatamount of a compound, material, or composition comprising a compound ofthe present invention which is effective for producing some desiredtherapeutic effect by inhibition of DAAO in at least a sub-population ofcells in an animal and thereby blocking the biological consequences ofthat pathway in the treated cells, at a reasonable benefit/risk ratioapplicable to any medical treatment.

The term “preventing” as used herein refers to administering amedicament beforehand to forestall or obtund an attack. The person ofordinary skill in the medical art (to which the present method claimsare directed) recognizes that the term “prevent” is not an absoluteterm. In the medical art it is understood to refer to the prophylacticadministration of a drug to substantially diminish the likelihood orseriousness of a condition, and this is the sense intended herein.

In various embodiments, the compounds of the invention also includepharmaceutically acceptable salts of the structures set forth herein.The term “pharmaceutically acceptable salts” includes salts of theactive compounds which are prepared with relatively nontoxic acids orbases, depending on the particular substituents found on the compoundsdescribed herein. When compounds of the present invention containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts includesodium, potassium, calcium, ammonium, organic amino, or magnesium salt,or a similar salt. When compounds of the present invention containrelatively basic functionalities, acid addition salts can be obtained bycontacting the neutral form of such compounds with a sufficient amountof the desired acid, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable acid addition salts includethose derived from inorganic acids like hydrochloric, hydrobromic,nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge et al., Journal of Pharmaceutical Science,66: 1-19 (1977)). Certain specific compounds of the present inventioncontain both basic and acidic functionalities that allow the compoundsto be converted into either base or acid addition salts.

When a residue is defined as “O⁻”, then the formula is meant tooptionally include an organic or inorganic cationic counterion.Preferably, the resulting salt form of the compound is pharmaceuticallyacceptable. The radicals —COOH, D, SO₃H include both the protonated andsalt forms of the acid.

The neutral forms of the compounds are optionally regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compound candiffer from the various salt forms with respect to certain physicalproperties, e.g., solubility in polar solvents. For exemplary compoundsof the invention, the salts are equivalent to the parent form of thecompound in terms of their general therapeutic utility.

The term “neurological disorder” refers to any condition of the centralor peripheral nervous system of a mammal. The term “neurologicaldisorder” includes neurodegenerative diseases (e.g., Alzheimer'sdisease, Parkinson's disease and amyotrophic lateral sclerosis),neuropsychiatric diseases (e.g. Schizophrenia and anxieties, such asgeneral anxiety disorder). Exemplary neurological disorders include MLS(cerebellar ataxia), Huntington's disease, Down syndrome, multi-infarctdementia, status epilecticus, contusive injuries (e.g. spinal cordinjury and head injury), viral infection induced neurodegeneration,(e.g. AIDS, encephalopathies), epilepsy, benign forgetfulness, closedhead injury, sleep disorders, depression (e.g., bipolar disorder),dementias, movement disorders, psychoses, alcoholism, post-traumaticstress disorder and the like. “Neurological disorder” also includes anycondition associated with the disorder. For instance, a method oftreating a neurodegenerative disorder includes methods of treating lossof memory and/or loss of cognition associated with a neurodegenerativedisorder. Such method would also include treating or preventing loss ofneuronal function characteristic of neurodegenerative disorder.

“Pain” is an unpleasant sensory and emotional experience. Painclassifications have been based on duration, etiology orpathophysiology, mechanism, intensity, and symptoms. The term “pain” asused herein refers to all categories of pain, including pain that isdescribed in terms of stimulus or nerve response, e.g., somatic pain(normal nerve response to a noxious stimulus) and neuropathic pain(abnormal response of a injured or altered sensory pathway, oftenwithout clear noxious input); pain that is categorized temporally, e.g.,chronic pain and acute pain; pain that is categorized in terms of itsseverity, e.g., mild, moderate, or severe; and pain that is a symptom ora result of a disease state or syndrome, e.g., inflammatory pain, cancerpain, AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiacischaemia, and diabetic peripheral neuropathic pain (see, e.g.,Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al.,eds., 12th ed. 1991); Williams et al., J. of Med. Chem. 42: 1481-1485(1999), herein each incorporated by reference in their entirety). “Pain”is also meant to include mixed etiology pain, dual mechanism pain,allodynia, causalgia, central pain, hyperesthesia, hyperpathia,dysesthesia, and hyperalgesia.

“Somatic” pain, as described above, refers to a normal nerve response toa noxious stimulus such as injury or illness, e.g., trauma, burn,infection, inflammation, or disease process such as cancer, and includesboth cutaneous pain (e.g., skin, muscle or joint derived) and visceralpain (e.g., organ derived).

“Neuropathic pain” is a heterogeneous group of neurological conditionsthat result from damage to the nervous system. “Neuropathic” pain, asdescribed above, refers to pain resulting from injury to or dysfunctionsof peripheral and/or central sensory pathways, and from dysfunctions ofthe nervous system, where the pain often occurs or persists without anobvious noxious input. This includes pain related to peripheralneuropathies as well as central neuropathic pain. Common types ofperipheral neuropathic pain include diabetic neuropathy (also calleddiabetic peripheral neuropathic pain, or DN, DPN, or DPNP),post-herpetic neuralgia (PHN), and trigeminal neuralgia (TGN). Centralneuropathic pain, involving damage to the brain or spinal cord, canoccur following stroke, spinal cord injury, and as a result of multiplesclerosis. Other types of pain that are meant to be included in thedefinition of neuropathic pain include pain from spinal cord injury,neuropathic cancer pain, HIV/AIDS induced pain, phantom limb pain, andcomplex regional pain syndrome. In a preferred embodiment, the compoundsof the invention are of use for treating neuropathic pain. An exemplarycompound of use in this embodiment is a compound according to Formula Iin which each of R¹-R³ is hydrogen, and R⁴ is selected such that thecompound is a free acid or salt thereof.

Common clinical features of neuropathic pain include sensory loss,allodynia (non-noxious stimuli produce pain), hyperalgesia andhyperpathia (delayed perception, summation, and painful aftersensation).Pain is often a combination of nociceptive and neuropathic types, forexample, mechanical spinal pain and radiculopathy or myelopathy.

“Acute pain” is the normal, predicted physiological response to anoxious chemical, thermal or mechanical stimulus typically associatedwith invasive procedures, trauma and disease. It is generallytime-limited, and can be viewed as an appropriate response to a stimulusthat threatens and/or produces tissue injury. “Acute pain”, as describedabove, refers to pain which is marked by short duration or sudden onset.

“Chronic pain” occurs in a wide range of disorders, for example, trauma,malignancies and chronic inflammatory diseases such as rheumatoidarthritis. Chronic pain usually lasts more than about six months. Inaddition, the intensity of chronic pain can be disproportionate to theintensity of the noxious stimulus or underlying process. “Chronic pain”,as described above, refers to pain associated with a chronic disorder,or pain that persists beyond resolution of an underlying disorder orhealing of an injury, and that is often more intense than the underlyingprocess would predict. It may be subject to frequent recurrence.

“Inflammatory pain” is pain in response to tissue injury and theresulting inflammatory process. Inflammatory pain is adaptive in that itelicits physiologic responses that promote healing. However,inflammation may also affect neuronal function. Inflammatory mediators,including PGE₂ induced by the COX2 enzyme, bradykinins, and othersubstances, bind to receptors on pain-transmitting neurons and altertheir function, increasing their excitability and thus increasing painsensation. Much chronic pain has an inflammatory component.“Inflammatory pain”, as described above, refers to pain which isproduced as a symptom or a result of inflammation or an immune systemdisorder.

“Visceral pain”, as described above, refers to pain which is located inan internal organ.

“Mixed etiology” pain, as described above, refers to pain that containsboth inflammatory and neuropathic components.

“Dual mechanism” pain, as described above, refers to pain that isamplified and maintained by both peripheral and central sensitization.

“Causalgia”, as described above, refers to a syndrome of sustainedburning, allodynia, and hyperpathia after a traumatic nerve lesion,often combined with vasomotor and sudomotor dysfunction and latertrophic changes.

“Central” pain, as described above, refers to pain initiated by aprimary lesion or dysfunction in the central nervous system.

“Hyperesthesia”, as described above, refers to increased sensitivity tostimulation, excluding the special senses.

“Hyperpathia”, as described above, refers to a painful syndromecharacterized by an abnormally painful reaction to a stimulus,especially a repetitive stimulus, as well as an increased threshold. Itcan occur with allodynia, hyperesthesia, hyperalgesia, or dysesthesia.

“Dysesthesia”, as described above, refers to an unpleasant abnormalsensation, whether spontaneous or evoked. Special cases of dysesthesiainclude hyperalgesia and allodynia,

“Hyperalgesia”, as described above, refers to an increased response to astimulus that is normally painful. It reflects increased pain onsuprathreshold stimulation.

“Allodynia”, as described above, refers to pain due to a stimulus thatdoes not normally provoke pain.

The term “Diabetic Peripheral Neuropathic Pain” (DPNP, also calleddiabetic neuropathy, DN or diabetic peripheral neuropathy) refers tochronic pain caused by neuropathy associated with diabetes mellitus. Theclassic presentation of DPNP is pain or tingling in the feet that can bedescribed not only as “burning” or “shooting” but also as severe achingpain. Less commonly, patients may describe the pain as itching, tearing,or like a toothache. The pain may be accompanied by allodynia andhyperalgesia and an absence of symptoms, such as numbness.

The term “Post-Herpetic Neuralgia”, also called “Postherpetic Neuralgia”(PHN), is a painful condition affecting nerve fibers and skin. It is acomplication of shingles, a second outbreak of the varicella zostervirus (VZV), which initially causes chickenpox.

The term “neuropathic cancer pain” refers to peripheral neuropathic painas a result of cancer, and can be caused directly by infiltration orcompression of a nerve by a tumor, or indirectly by cancer treatmentssuch as radiation therapy and chemotherapy (chemotherapy-inducedneuropathy).

The term “HIV/AIDS peripheral neuropathy” or “HIV/AIDS-relatedneuropathy” refers to peripheral neuropathy caused by HIV/AIDS, such asacute or chronic inflammatory demyelinating neuropathy (AIDP and CIDP,respectively), as well as peripheral neuropathy resulting as a sideeffect of drugs used to treat HIV/AIDS.

The term “Phantom Limb Pain” refers to pain appearing to come from wherean amputated limb used to be. Phantom limb pain can also occur in limbsfollowing paralysis. It is usually chronic in nature. It is similar innature to the limb pain experienced by patients with paralysis followingspinal cord injury.

The term “Trigeminal Neuralgia” (TN) refers to a disorder of the fifthcranial (trigeminal) nerve that causes episodes of intense, stabbing,electric-shock-like pain in the areas of the face where the branches ofthe nerve are distributed (lips, eyes, nose, scalp, forehead, upper jaw,and lower jaw). It is also known as the “suicide disease”.

The term “Complex Regional Pain Syndrome (CRPS),” formerly known asReflex Sympathetic Dystrophy (RSD), is a chronic pain condition. The keysymptom of CRPS is continuous, intense pain out of proportion to theseverity of the injury, which gets worse rather than better over time.CRPS is divided into type 1, which includes conditions caused by tissueinjury other than peripheral nerve, and type 2, in which the syndrome isprovoked by major nerve injury, and is sometimes called causalgia.

The term “fibromyalgia” refers to a chronic condition characterized bydiffuse or specific muscle, joint, or bone pain, along with fatigue anda range of other symptoms. Previously, fibromyalgia was known by othernames such as fibrositis, chronic muscle pain syndrome, psychogenicrheumatism and tension myalgias.

The term “convulsion” refers to a CNS disorder and is usedinterchangeably with “seizure;” there are many types of seizure, some ofwhich have subtle or mild symptoms instead of convulsions. Seizures ofall types may be caused by disorganized and sudden electrical activityin the brain. Convulsions are a rapid and uncontrollable shaking Duringconvulsions, the muscles contract and relax repeatedly.

The term “method of treating pain” means a method providing to a subjecta measure of relief from the symptoms or the prevention of pain, whichincludes the descriptions of pain provided herein. Additional examplesinclude, but are not limited to, migraine, chronic back pain, phantomlimb pain, neuropathic pain such as diabetic neuropathy, and postherpetic neuropathy.

The term “method of treating anxiety disorders” as used herein means amethod of providing to a subject a measure of relief from the symptom ofanxiety, or a method preventing anxiety. Anxiety disorders include, butare not limited to, panic disorder with or without agoraphobia,agoraphobia without history of panic disorder, animal or other phobiasincluding social phobias, obsessive-compulsive disorder, stressdisorders including post-traumatic and acute stress disorder,situational anxiety, generalized anxiety disorder and substance-inducedanxiety disorder.

The term “method of treating psychotic disorders” as used herein means amethod of providing to a subject a measure of relief from the symptomsof a psychotic disorder, or preventing a psychotic disorder. Psychoticdisorders include, but are not limited to, schizophrenia,schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to general medical condition, substance-induced psychoticdisorder, or psychotic disorder not otherwise specified (Diagnostic andStastistical Manual of Mental Disorders, (Ed. 4^(th)) AmericanPsychiatric Association, Washington, D.C. (1994)).

The term “method of treating convulsive disorders” means a method ofproviding to a subject a measure of relief from the symptoms of aconvulsive disorder, e.g., epilepsy, or preventing a convulsivedisorder. Convulsive disorders include, but are not limited to, alteredconsciousness, altered motor activity, autonomic responses,inappropriate behavior patterns seizures including tonic or clonicjerking of extremities, emotional stress, sense of terror, uneasiness,nervousness, headache, fatigue, auditory hallucinations, aggressiveoutbursts, acute skeletal muscle spasm, and spasticity.

The term “method of treating depressive or bipolar disorders”, as usedherein, means a method of providing a measure of relief to a subjectfrom the symptoms of, or preventing, depressive disorders, whichinclude, but are not limited to, single-episode or recurrent majordepressive disorder, seasonal affective disorder (SAD), dysthymicdisorder, bipolar I and bipolar II manic disorders, and cyclothymicdisorder.

The term “method of treating cognitive disorders” means a method ofproviding to a subject a measure of relief from the symptoms of acognitive disorder, or of preventing a cognitive disorder. Cognitivedisorders include, but are not limited to delirium, dementia, amnesicdisorders, and cognitive deficits, memory deficits, includingage-related memory deficits, and deficits due to traumatic injury,stroke, Parkinson's disease, attention deficit disorder and DownsSyndrome. Cognitive disorders may also be attributable to substanceabuse or withdrawal. Examples of dementia include dementia of theAlzheimer's type with early or late onset, and vascular dementia, any ofwhich may be uncomplicated or accompanied by delirium, delusions ordepressed mood; and dementia due to HIV virus, head trauma, Parkinson'sdisease or Creutzfeld-Jakob disease.

The term “method of treating sleeping disorders”, as used herein, meansa method providing to a subject a measure of relief from the symptomsof, or preventing, sleep disorders or states that affect a subject'sability to sleep, which includes, but are not limited to, insomnia,sleep apnea, REM sleep interruptions, parasomnia, jet-lag syndrome,hypersomnia, shift workers' sleep disturbances, dysomnias, night terror,narcolepsy, disturbed sleep patterns, disturbed biological or circadianrhythms, sleep disturbances associated with such diseases asneurological disorders, neuropathic pain and restless leg syndrome, orproviding sleep induction before surgical procedures or in disturbed oranxious states.

The term “method of treating neurodegenerative eye diseases”, as usedherein, means a method providing to a subject a measure of relief ofsymptoms of, or preventing, neurodegenerative eye diseases, whichinclude, but are not limited to retinoschisis, vascular diseases of theretina, diseases caused by venous and/or arterial vascular occlusions,macular degenerations, traumatic retinal changes such as contusion ofthe eye, perforating eye injuries, siderosis/hemidosis, chalcosis,burns, retinopathia traumatica and/or injury to the retina from light,diseases of the choroid, diseases of the optic nerve, anterior ischemicoptic neuropathy, optic atrophy, glaucoma, glaucoma simplex, secondaryglaucoma and/or ocular hypertension.

The term “method of treating emesis” means a method of providing asubject a measure of relief from the symptoms of, or preventing, emesis,which includes, but is not limited to, acute, delayed and anticipatoryemesis, emesis induced by chemotherapy or radiation, as well as motionsickness, and post-operative nausea and vomiting.

The term “method of treating eating disorders” means relief from thesymptoms of, or preventing, eating disorders, which include, but are notlimited to, anorexia nervosa, bulimia nervosa, obesity, weight-gainafter smoking cessation, snacking and binge eating.

The term “benzodiazepine receptor” as used herein, includes thebenzodiazepine receptor/GABA receptor/chloride channel complex(benzodiazepine receptor complex) and benzodiazepine receptor-agonistbinding sites at or near the receptor complex. Both central nervoussystem (“central”) and peripheral benzodiazepine receptors(“peripheral”) are encompassed by the use of this term.

The term “IC₅₀” refers to the concentration causing a 50% inhibition ofthe specific binding of the control substance.

II. Compounds

In various embodiments, the present invention provides a compound havinga structure according to Formula I:

In Formula I, R¹, R², R³ and R⁴ are each independently selected from H,D, halogen, hydroxyl, dialkylamino, cyano, sulfonamide, acyl,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl. Thesymbols R⁵ and R⁶ represent members independently selected from H; F;hydroxyl; substituted or unsubstituted alkoxy and lower alkyl. Q isselected from:

Ring system A is an optionally substituted 4, 5, 6 or 7 membermonocyclic or 8, 9, 10, 11 or 12 member bicyclic ring comprising 0, 1,2, 3 or 4 heteroatoms independently selected from N, O and S. The symbolX represents O, S or NR⁷. R⁷ is selected from H; substituted orunsubstituted alkyl; substituted or unsubstituted heteroalkyl;substituted or unsubstituted cycloalkyl; substituted or unsubstitutedheterocycloalkyl; substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl. Y is a member selected from a bond,(CR⁸R⁹)_(n), O, S, NR¹⁰R¹¹, S(O), S(O)₂, S(O)_(p)NR¹⁰R¹¹,(CR⁸R⁹)_(n)G(CR⁸R⁹)_(m). G is a member selected from a bond and O. Theindeces m and n are independently selected integers from 0 to 4. EachR⁸, R⁹ and R¹⁰ are independently selected from H, D, substituted orunsubstituted alkyl, acyl, SO₂R^(8a), OR^(8a), COOR^(8a), andCONR^(8a)R^(8b). R^(8a) and R^(8b) are independently selected from H, D,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl. R⁸ and R⁹, R^(8a) and R^(8b)are optionally joined in a ring, or both these pairs of radicals areoptionally joined into rings. The index n is the integer 0, 1, 2, 3 or4. R⁸, R⁹ and R¹⁰ are independently H, D, substituted or unsubstitutedalkyl, acyl, SO₂R^(8a), OR^(8a), COOR^(8a), or CONR^(8a)R^(8b). Thesymbols R^(8a) and R^(8b) independently represent H, D, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. R¹¹ is selected from a bond and NR^(11a).R^(11a) is selected from H, D, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl and substituted or unsubstituted heteroaryl. Z isCR¹² or N. R¹² is H, D, halogen, substituted or unsubstituted alkyl;substituted or unsubstituted heteroalkyl; substituted or unsubstitutedcycloalkyl; substituted or unsubstituted heterocycloalkyl; substitutedor unsubstituted aryl or substituted or unsubstituted heteroaryl.

Exemplary compounds according to Formula I can be conveniently dividedinto subgenera based on the identity of Q. The structures of theseexemplary subgenera are shown below:

in which the substituents are as set forth above in the description ofFormula I.

In an exemplary embodiment A comprises at least two endocyclic nitrogenatoms. In exemplary embodiments, A comprises 2 or 3 endocyclic nitrogenatoms. In various embodiments, A is a a six-member ring system with twoendocyclic nitrogen atoms, a five-member ring system with two endocyclicnitrogen atoms, a five-member ring with two endocyclic nitrogen atomsand an endocyclic oxygen atom, or a five-member ring system with threeendocyclic nitrogen atoms.

In various embodiments according to Formula I, ring system A is selectedfrom substituted or unsubstituted thiadiazolyl; substituted orunsubstituted pyridazinyl; substituted or unsubstituted oxadiazolyl;substituted or unsubstituted triazinyl; substituted or unsubstitutedpyrazolyl; substituted or unsubstituted pyrimidinyl; substituted orunsubstituted triazolyl; substituted or unsubstituted benzoimidazolyl;substituted or unsubstituted indolinyl; substituted or unsubstitutedfuropyrrolyl; substituted or unsubstituted indolyl; substituted orunsubstituted benzotriazolyl; substituted or unsubstitutedbenzooxazolyl; substituted or unsubstituted pyridinyl; substituted orunsubstituted tetrazolyl; substituted or unsubstituted thiazolyl;substituted or unsubstituted indazolyl; substituted or unsubstituteddiazolyl; substituted or unsubstituted purinyl; substituted orunsubstituted pyrazinyl; substituted or unsubstituted imidazopyridinyl;substituted or unsubstituted benzooxazinyl; substituted or unsubstitutedoxazolyl; substituted or unsubstituted benzyl; substituted orunsubstituted benzothiadiazonyl; substituted or unsubstitutedthiopheneyl; substituted or unsubstituted quinolinyl; substituted orunsubstituted quinazolinyl; substituted or unsubstituted oxazolidinyl;substituted or unsubstituted imidazolidinyl and substituted orunsubstituted azetidinyl.

In an exemplary embodiment, ring system A comprises at least onesubstituent selected from OCH₃; CH₂CH₃; NHCH₃; CH₃; H; ═O; Cl;C═OOCH₂CH₃; —CN; Br; F; CF₃; NH₂; SCH₃; S═OCH₃; CHCH₂; NCH₃CH₃;OCH₂CH₂NCH₃CH₃; NHCH₂CH₂NCH₃CH₃; C(H)(OCH₃)(OCH₃); OCH₂CH₃;OCH₂CH₂NHCH₃; CH₂NCH₃CH₃; NHC═OCH₃; 4-methylpiperazinyl;1-(t-butoxycarbonyl)azetidin-3-oxy; azetidin-3-oxy; pyrrolidinaminyl;NHNCH₃CH₃; CH₂SCH₃; (S)—(N-methylpyrrolidin-2-yl)methoxy;(N-methylpyrrolidin-3-yl)methoxy; CH₂OH; NHNH₂; N-methylpiperidinyloxy;NNH₂CH₃; CH₂C═ONHCH₃; N(C═OCH₃)(NHC═OCH₃); piperidin-4-ol-1-yl;(N-methylpyrrolidin-2-yl)methoxy; OCHCH₃CH₂NCH₃CH₃; piperidin-4-oxy;N-methylpyrrolidin-3-yl; CH₂NHCH₂CH₃; CH₂NCH₃CH₂CH₃;1-t-butoxycarbonylpyrrolidin-2-yl; pyrrolidin-2-yl; pyrrolidinylmethyl;S-2-hydroxymethylpyrrolidinyl; 3-hydroxypyrrolidinyl;R—N-pyrrolidin-3-yloxy; S—N-pyrrolidin-3-yloxy;4-hydroxy-4-methyl-piperidinyl; ═S; CH₂C═OOCH₃; CH₂CH₂NCH₃CH₃; C═OOCH₃;C═OCH₂CH₃; phenyl; C═ONCH₃CH₃; CHCH₃CH₃; C═OH; C═OOCHCH₃; C═ONHCH₃;C═ONH₂; 3-methyl-1,2,4-diazole-5-yl; C═ONHCH₂CH₂NCH₃CH₃; C═OCH₂;2-pyridinyl; ═NH; 2-furanyl; 3-pyridyl; p-methylbenzyl; C═OOH;═ONCH₃OCH₃; C═OOC(H)(CH₃)(CH₃); C(OH)(CH₃)(CH₃); CH₃OH; C═OCH₃;C═OOCCH₃CH₃CH₃; C═OOCCCH₃CH₃CH₃; COOCH₃; CH₂NHCH₃; ═ONHCH₂CH₂NCH₃CH₃;3-hydroxpyrrolidinyl; NCH₃CH₂CH₂OH; NHNHCH₃; 3-pyrrolidinoxy;1,2,4-triazolyl; pyrrolidinyl and NHCH₂CH₃.

In various embodiments, A is substituted with a moiety having theformula:

In the formula above, R^(a) is OR^(b), NR^(b)R^(c), or NHNH₂, whereinR^(b) is H, D, or substituted or unsubstituted alkyl. The symbol R^(c)represents H, D, OR^(d) or substituted or unsubstituted alkyl. R^(d) isH or substituted or unsubstituted alkyl. In various embodiments, atleast one of R^(a) and R^(b) is other than H.

In certain embodiments according to Formula I, the invention provides acompound having a structure according to Formula VI:

R¹, R², R³ and R⁴ are each members independently selected from H, D,halogen, hydroxyl, dialkylamino, cyano, sulfonamide, acyl, substitutedor unsubstituted alkyl, substituted or unsubstituted alkoxy, substitutedor unsubstituted heterocycloalkyl, substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl. The symbol Y represents a bond,NH, D, S, and O such that when Y is a bond, it binds A directly to themethylene moiety pendant from the ring. The symbol A is as describedhereinabove.

In certain embodiments, according to Formula VI, R² is H, D and R⁴ is H,D, substituted or unsubstituted alkyl or halogen. In variousembodiments, R¹ is H, D and R³ is H, D, substituted or unsubstitutedalkyl or halogen. In exemplary embodiments, R⁴ is halogen and R³ is H,D, methyl or halogen.

In various embodiments according to Formula I, the invention provides acompound having a structure according to Formula VII:

in which the substituents are as described for Formula VI.

In exemplary embodiments according to Formula I, in compounds accordingto Formula VI and VII, Y-A has a formula selected from Table 1:

TABLE 1

In exemplary compounds of Formula I, R⁵ and R⁶ are hydrogen. Q is

and A is imidazol-1-yl, 2-methylimidazol-1-yl, 2-ethylimidazol-1-yl,2-isopropylimidazol-1-yl, 2-phenylimidazol-1-yl,2-(N,N-dimethyl)aminocarbonylimidazol-1-yl,2-methoxycarbonylimidazol-1-yl, 2-ethoxycarbonylimidazol-1-yl,4,5-dichloroimidazol-1-yl, pyrazol-1-yl, 3,5-dimethylpyrazol-1-yl,1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl,3-methoxycarbonyl-1,2,4-triazol-1-yl,5-methoxycarbonyl-1,2,4-triazol-1-yl,5-isopropyloxycarbonyl-1,2,4-triazol-1-yl,5-hydroxycarbonyl-1,2,4-triazol-1-yl,5-methylaminocarbonyl-1,2,4-triazol-1-yl,5-methyl(methoxy)aminocarbonyl-1,2,4-triazol-1-yl,5-aminocarbonyl-1,2,4-triazol-1-yl,5-dimethylaminocarbonyl-1,2,4-triazol-1-yl, 5-methyltetrazol-1-yl,5-methyltetrazol-2-yl, 6-(N,N-dimethylamino)-purin-9-yl,2-methylbenzimidazol-1-yl, benzotriazol-2-yl, imidazopyridin-1-yl,azetidin-2-one-1-yl, pyrrolidin-2-one-1-yl,3-ethyl-4-methyl-pyrrol-2(5H)-one-1-yl, 4-methoxypyrrol-2(5H)-one-1-yl,1,2-dihydro-5-methylpyrazol-3-one-2-yl, oxazolidin-2-one-3-yl,piperidin-2-one-1-yl, 4,5-dimethylpyridazin-3-one-2-yl,pyridine-2-one-1-yl, 3-methyl-pyridine-2-one-1-yl,6-methylpyridine-2-one-1-yl, 5-chloropyridine-2-one-1-yl,6-methylpyridazin-3-one-2-yl, pyrimidin-2-one-1-yl,pyrimidin-4-one-3-yl, pyrimidin-2-thione-1-yl,5,5-dimethyloxazolidin-2,4-dione-3-yl,1-methylimidazolidine-2,4-dione-3-yl, thiazol-2-one-3-yl,4,5-dimethylthiazol-2-one-3-yl,3-(methylthio)-1,2,4-thiadiazol-5-one-4-yl,isoindolin-1,3-dione-2-yloxy, benzo[1,2,3]triazol-1-yloxy,pyrimidin-2-ylamino, 4,6-dimethylpyrimidin-2-ylamino,4,6-dichloropyrimidin-2-ylamino, 5-bromopyrimidin-2-ylamino,4-methylpyrimidin-2-ylamino, pyrazin-2-ylamino, 1,3,5-triazin-2-ylamino,1,2,4-triazin-3-ylamino, pyridin-2-ylamino, 3-chloropyridin-6-ylamino,3,5-dichloropyridin-2-ylamino, 1,3,4-thiadiazol-2-ylamino,thiazol-2ylamino, 3-methyl-thiazol-5ylamino,3-methylisothiazol-5-ylamino, isoxazol-3ylamino,1,2,4-triazol-4-ylamino, imidazolin-2-ylamino,4-methyl-1,2,4-triazol-3-ylthio, 2-methyl-1,3,4-thiadizol-5-ylthio,1,3,4-thiadizol-2-ylthio, 4,6-dimethylpyrimidin-2-ylthio,1-methylbenzimidazol-2-ylthio, oxazolo[4,5-b]pyridine-2-ylthio,1,2,4-triazol-3-ylthio or phenylthio.

In various exemplary compounds according to Formula I, R⁴ is hydrogenand R² is at the 4′-position and is selected from the group consistingof methyl, chloro, fluoro, bromo or H.

In various exemplary compounds according to Formula I, R¹ is at the6-position of the H-imidazol[1,2-a]pyridine ring and is selected fromthe group consisting of methyl, chloro, fluoro, bromo or H. In anexemplary embodiment, and Z is CH

In some embodiments according to Formula I, R³ is at the 8-position ofthe H-imidazo[1,2-a]pyridine ring and is selected from the groupconsisting of chloro; fluoro and H. In an exemplary embodiment, and Z isCH.

In various embodiments according to Formula I, compounds are provided inwhich Q is a member selected from:

In various embodiments according to Formula I, the invention providescompounds having the structure:

in which R¹³, R¹⁴ and R¹⁵ are members independently selected frommethyl; chlorine; fluorine; bromine and hydrogen, and Q is as describedabove.

In various embodiments according to this formula, Q is selected from:

In an exemplary embodiment according to Formula I, Y is a bond. Thus, inexemplary compounds, the C-3 carbon of the imidazo[1,2-a]pyridine isdirectly attached to the carbon of CR⁵R⁶, which carbon is directlyattached to an atom of the backbone ring A. In various embodiments, theC-3 carbon of the imidazo[1,2-a]pyridine is directly attached to thecarbon of CR⁵R⁶, which carbon is directly attached to a carbon of thebackbone ring A as disclosed herein.

In various embodiments according to Formula I, Y is a bond and Q issubstituted or unsubstituted pyrrolyl, diazolyl, triazolyl ortetrazolyl. In an exemplary embodiment, Q is substituted orunsubstituted 1,2,4-triazol-5-yl. In an exemplary embodiment, Q is1,2,4-triazol-5-yl substituted with an alkyl group. In an exemplaryembodiment, Q is 1-methyl-1,2,4-triazol-5-yl.

In an exemplary embodiment according to Formula I, Z is CH, D, Q is astructure as set forth herein, R¹ and R² are H, D and R³ and R⁴ areindependently selected halogen. In an exemplary embodiment according toFormula I, Z is CH, D, Q is a structure as set forth herein, R¹ and R²,R⁵ and R⁶ are H, D, R³ and R⁴ and are independently selected halogen. Inan exemplary embodiment according to Formula I, Z is CH, D, Q is astructure as set forth herein, R¹, R², R⁵ and R⁶ are H, D, and R³ and R⁴are F. In an exemplary embodiment according to Formula I, Z is CH, D, Qis 1-methyl-1,2,4-triazol-5-yl, R¹, R², R⁵ and R⁶ are H, D, R³ is F atposition 6, and R⁴ is F at position 4′.

The invention also provides compounds having a structure selected from:

R¹⁶ and R¹⁷ are independently selected from H, D, halogen, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl andNR¹⁸R¹⁹, wherein R¹⁸ and R¹⁹ are substituted or unsubstituted alkyl. Theindex a is 1, 2 or 3. Q is selected from substituted or unsubstitutedheterocycloalkyl and substituted or unsubstituted heteroaryl. R¹⁸ andR¹⁹ are optionally joined in a ring. Exemplary rings include 5- and6-member rings.

In one embodiment, Q has the structure

—R²⁰-R²¹,

wherein R²⁰ is selected from a bond and NH; and R²¹ is selected fromsubstituted or unsubstituted heterocycloalkyl and substituted orunsubstituted heteroaryl.

In one embodiment, Q has a structure selected from

The present invention also provides compounds of having a structure:

R²² is selected from H; halogen and substituted or unsubstituted alkyl;R²³, R²⁴ and R²⁶ is selected from H, D and halogen; R²⁵ is selected fromH; halogen; substituted or unsubstituted alkyl; substituted orunsubstituted heteroalkyl and substituted or unsubstituted aryl; R²⁷ isselected from H; substituted or unsubstituted alkyl and OR²⁸, whereinR²⁸ is selected from H, D and substituted or unsubstituted alkyl; and Qis selected from substituted or unsubstituted cycloalkyl; substituted orunsubstituted heterocycloalkyl; substituted or unsubstituted aryl;substituted or unsubstituted heteroaryl; substituted or unsubstitutedarylalkyl and substituted or unsubstituted heteroarylalkyl. Z isselected from CR¹² and N, wherein R¹² is selected from H; substituted orunsubstituted alkyl; substituted or unsubstituted heteroalkyl;substituted or unsubstituted cycloalkyl; substituted or unsubstitutedheterocycloalkyl; substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl.

In one embodiment, Q has the structure

—R²⁹-R³⁰.

R²⁹ is selected from a bond, substituted or unsubstituted alkyl, S, O,C(O), S(O) and NR^(29a)R^(29b). R^(29a) is selected from H, D and alkyl.R^(29b) is selected from a bond and NR^(29c). R²⁹ and R^(29a) areoptionally joined in a ring. Exemplary rings include 5- and 6-memberrings. R³⁰ is selected from substituted or unsubstituted cycloalkyl;substituted or unsubstituted heterocycloalkyl; substituted orunsubstituted aryl; substituted or unsubstituted heteroaryl; substitutedor unsubstituted arylalkyl and substituted or unsubstitutedheteroarylalkyl.

In one embodiment, R³⁰ has the structure:

The symbols Z¹, Z², Z³, Z⁴ and Z⁵ independently represent C, N, O, andS. The index b is 0 or 1. The symbols R³¹, R³², R³³, R³⁴ and R³⁵independently represent nil, H, D, heteroatom, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, ═NH, D, ═O, ═S, C(O)R³⁶ or SR³⁷. R³⁴ and R³⁵are optionally joined in a ring. An exemplary ring is a 5-member or a6-member ring. R³⁶ is a group selected from H; substituted orunsubstituted alkyl, NR^(36a)R^(36b) and OR^(36c). R^(36a) and R^(36b)are independently H, D, substituted or unsubstituted alkyl orsubstituted or unsubstituted heteroalkyl. R^(36a) and R^(36b) areoptionally joined in a ring. An exemplary ring is a 5- or 6-member ring.R^(36a) is H or substituted or unsubstituted alkyl. R³⁷ is substitutedor unsubstituted alkyl. R³² and R³³, together with the atoms to whichthey are attached are optionally joined to form a 5- or 6-member ring.R³³ and R³⁴, together with the atoms to which they are attached, areoptionally joined to form a 5- or 6-member ring.

In one embodiment, R³⁰ has the structure

Z¹, Z², Z³, Z⁴, Z⁵, and Z⁶ are independently selected from C, N, O andS. The index b is 0 or 1, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴³ areindependently selected from nil, H, D, heteroatom, halogen, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, ═NH, ═O, ═S, C(O)R⁴⁴ and SR⁴⁵. R⁴² and R⁴³ areoptionally joined in a ring, e.g., a 5- or 6-member ring. R⁴⁴ isselected from H, D, substituted or unsubstituted alkyl, NR^(44a)R^(44b)and OR^(44c), wherein R^(44a) and R^(44b) are independently selectedfrom H, D, substituted or unsubstituted alkyl and substituted orunsubstituted heteroalkyl, and R^(44a) is selected from H, D andsubstituted or unsubstituted alkyl, and R⁴⁵ is selected from substitutedor unsubstituted alkyl. R³⁹ and R⁴⁰ are optionally joined to form a 5-or 6-member ring including the atoms to which they are attached. R⁴⁰ andR⁴¹ are optionally joined to form a 5 or 6 membered ring including theatoms to which they are attached. R⁴¹ and R⁴² are optionally joined toform a 5- or 6-member ring including the atoms to which they areattached.

In one embodiment, R³⁰ comprises at least one substituent selected fromthe group OCH₃, CH₂CH₃, NHCH₃, CH₃, H, D, ═O, Cl, C═OOCH₂CH₃, —CN, Br,F, CF₃, NH₂, SCH₃, S═OCH₃, CHCH₂, NCH₃CH₃, OCH₂CH₂NCH₃CH₃,NHCH₂CH₂NCH₃CH₃, OCH₂CH₃, OCH₂CH₂NHCH₃, CH₂NCH₃CH₃, NHC═OCH₃,4-methylpiperazinyl, 1-(t-butoxycarbonyl)azetidin-3-oxy, azetidin-3-oxy,pyrrolidinaminyl, NHNCH₃CH₃, CH₂SCH₃,(S)—(N-methylpyrrolidin-2-yl)methoxy, (N-methylpyrrolidin-3-yl)methoxy,CH₂OH, NHNH₂, N-methylpiperidinyloxy, NHNHCH₃, CH₂C═ONHCH₃,N(C═OCH₃)(NHC═OCH₃), piperidin-4-ol-1-yl,(N-methylpyrrolidin-2-yl)methoxy, OCHCH₃CH₂NCH₃CH₃, piperidin-4-oxy,N-methylpyrrolidin-3-yl, CH₂NHCH₂CH₃, CH₂NCH₃CH₂CH₃,1-t-butoxycarbonylpyrrolidin-2-yl, pyrrolidin-2-yl, pyrrolidinylmethyl,S-2-hydroxymethylpyrrolidinyl, 3-hydroxypyrrolidinyl,R—N-pyrrolidin-3-yloxy, S—N-pyrrolidin-3-yloxy,4-hydroxy-4-methyl-piperidinyl, ═S, CH₂C═OOCH₃, CH₂CH₂NCH₃CH₃, C═OOCH₃,C═OCH₂CH₃, phenyl, C═ONCH₃CH₃, CHCH₃CH₃, C═OH, C═OOCHCH₃, C═ONHCH₃,C═ONH₂, 3-methyl-1,2,4-diazole-5-yl, C═ONHCH₂CH₂NCH₃CH₃, C═OCH₂,2-pyridinyl, ═NH, 2-furanyl, 3-pyridyl, p-methylbenzyl, C═OOH,═ONCH₃OCH₃, C═OOC(H)(CH₃)(CH₃), C(OH)(CH₃)(CH₃), CH₃OH, C═OCH₃,C═OOCCH₃CH₃CH₃, C═OOCCCH₃CH₃CH₃, COOCH₃, CH₂NHCH₃, ═ONHCH₂CH₂NCH₃CH₃,3-hydroxpyrrolidinyl, NCH₃CH₂CH₂OH, NHNHCH₃, 3-pyrrolidinoxy,1,2,4-triazolyl, pyrrolidinyl and NHCH₂CH₃, C═ON(OH)CH₃, C═ONHOH,C═ONHNH₂, and C═ONHNCH₃CH₃.

In an exemplary embodiment, Q is selected from substituted orunsubstituted azetidine and substituted or unsubstituted imidazolidine.

The following compounds are illustrative of compounds of Formula II, butthe invention is not limited to the compounds listed herein:3-((1H-imidazol-1-yl)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine,6-methyl-3-((2-methyl-1H-imidazol-1-yl)methyl)-2-p-tolylH-imidazo[1,2-a]pyridine,3-((1H-pyrazol-1-yl)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine,6-methyl-3-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-2-p-tolylH-imidazo[1,2-a]pyridine,3-((1H-1,2,3-triazol-1-yl)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine,3-((1H-1,2,4-triazol-1-yl)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine,N,N-dimethyl-9-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-9H-purin-6-amine,1-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-imidazo[4,5-b]pyridine,6-methyl-3-((5-methyl-2H-tetrazol-2-yl)methyl)-2-p-tolylH-imidazo[1,2-a]pyridine,6-methyl-3-((5-methyl-1H-tetrazol-1-yl)methyl)-2-p-tolylH-imidazo[1,2-a]pyridine,3-((2-isopropyl-1H-imidazol-1-yl)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-c]pyridine,3-((4,5-dichloro-1H-imidazol-1-yl)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine,3-((2-ethyl-1H-imidazol-1-yl)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine,6-methyl-3-((2-phenyl-M-imidazol-1-yl)methyl)-2-p-tolylH-imidazo[1,2-a]pyridine,N,N-dimethyl-1-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-imidazole-2-carboxamide,2-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-2H-benzo[d][1,2,3]triazole,1-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-benzo[d]imidazole,3-((1H-1,2,4-triazol-1-yl)methyl)-6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridine,3-((1H-1,2,3-triazol-1-yl)methyl)-6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridine,methyl1-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate,methyl2-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-2H-1,2,4-triazole-3-carboxylate,3-((1H-pyrazol-1-yl)methyl)-6,8-dichloro-2-p-tolylH-imidazo[1,2-a]pyridine,3-((1H-1,2,3-triazol-1-yl)methyl)-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridine,3-((2H-1,2,3-triazol-2-yl)methyl)-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridine,3-((1H-1,2,3-triazol-1-yl)methyl)-6-chloro-2-phenylH-imidazo[1,2-a]pyridine,3-((2H-1,2,3-triazol-2-yl)methyl)-6-chloro-2-phenylH-imidazo[1,2-a]pyridine,3-((2H-1,2,3-triazol-2-yl)methyl)-6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridine,2-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-N-methyl-2H-1,2,4-triazole-3-carboxamide,methyl2-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-2H-1,2,4-triazole-3-carboxylate,methyl1-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate,methyl1-((2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate,methyl2-((6-chloro-2-phenylH-imidazo[1,2-a]pyridin-3-yl)methyl)-2H-1,2,4-triazole-3-carboxylate,methyl1-((6-chloro-2-phenylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate,2-((2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-N-methyl-2H-1,2,4-triazole-3-carboxamide,methyl2-((2-(4-chlorophenyl)H-imidazo[1,2-c]pyridin-3-yl)methyl)-2H-1,2,4-triazole-3-carboxylate,2-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-N-methoxy-N-methyl-2H-1,2,4-triazole-3-carboxamide,ethyl1-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-imidazole-2-carboxylate,2-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-2H-1,2,4-triazole-3-carboxamide,2-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-N,N-dimethyl-2H-1,2,4-triazole-3-carboxamide,ethyl1-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-imidazole-2-carboxylate,N-methyl-2-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-2H-1,2,4-triazole-3-carboxamide,N,N-dimethyl-2-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-2H-1,2,4-triazole-3-carboxamide,2-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-2H-1,2,4-triazole-3-carboxamide,isopropyl2-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-2H-1,2,4-triazole-3-carboxylate,and3-(1-(1H-1,2,4-triazol-1-yl)ethyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine,3-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carbohydrazide,3-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide,3-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide,ethyl3-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate,ethyl3-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate,ethyl3-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate,3-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-N-methyl-1,2,4-oxadiazole-5-carboxamide,3-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide,3-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N-methyl-1,2,4-oxadiazole-5-carboxamide,3-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-N-hydroxy-1,2,4-oxadiazole-5-carboxamide,3-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N-hydroxy-1,2,4-oxadiazole-5-carboxamide,3-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N-methoxy-1,2,4-oxadiazole-5-carboxamide,3-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N-hydroxy-N-methyl-1,2,4-oxadiazole-5-carboxamide,and3-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N-hydroxy-1,2,4-oxadiazole-5-carboxamide.

The following compounds are illustrative of compounds of Formula III,however, the invention is not limited to the compounds listed herein:1-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrrolidin-2-one,3-ethyl-4-methyl-1-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-pyrrol-2(5H)-one,4-methoxy-1-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-pyrrol-2(5H)-one,1,2-dihydro-3-methyl-1-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrazol-5-one,3-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)oxazolidin-2-one,1-methyl-3-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)imidazolidin-2-one,1-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)piperidin-2-one,1-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2(1H)-one,3-methyl-1-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2(1H)-one,6-methyl-2-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyridazin-3(2H)-one,4,5-dichloro-2-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyridazin-3(2H)-one,3-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-4(3H)-one,1-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-one,1-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)pyrrolidin-2-one,1-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-4-methoxy-1H-pyrrol-2(5H)-one,3-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)oxazolidin-2-one,1-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2(1H)-one,1-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-3-methylpyridin-2(1H)-one,1-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-6-methylpyridin-2(1H)-one,2-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-6-methylpyridazin-3(2H)-one,5-chloro-1-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2(1H)-one,1-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-4-methoxy-1H-pyrrol-2(5H)-one,1-methyl-3-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)imidazolidine-2,4-dione,1-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)azetidin-2-one,5,5-dimethyl-3-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)oxazolidine-2,4-dione,3-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)thiazole-2(3H)-thione,4,5-dimethyl-3-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)thiazole-2(3H)-thione,4-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-3-(methylthio)-1,2,4-thiadiazole-5(4H)-thione,1-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidine-2(1H)-thione,2-((6,8-dichloro-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-6-methylpyridazin-3(2H)-one,1-((6,8-dichloro-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrrolidin-2-one,1-((2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2(1H)-one,1-((6-chloro-2-phenylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2(1H)-one,and1-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)azetidin-2-one.

The following compounds are illustrative of compounds of Formula IV,however, the invention is not limited to the compounds listed herein:N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-triazin-3-amine,4-methyl-N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine,N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrazin-2-amine,N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine,4,6-dimethyl-N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine,4,6-dichloro-N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine,5-bromo-N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine,3,5-dichloro-N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2-amine,N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2-amine,N-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine,N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)isoxazol-3-amine,N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)thiazol-2-amine,3-methyl-N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)isothiazol-5-amine,(6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)-N-(4H-1,2,4-triazol-4-yl)methanamine,1-methyl-N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-benzo[d]imidazol-2-amine,5-chloro-N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2-amine,N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-imidazol-2-amine,1-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methoxy)-1H-benzo[d][1,2,3]triazole,2-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methoxy)isoindoline-1,3-dione,3-((4-methyl-4H-1,2,4-triazol-3-ylthio)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine,3-((1-methyl-1H-benzo[d]imidazol-2-ylthio)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine,3-((4H-1,2,4-triazol-3-ylthio)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine,6-methyl-3-((phenylthio)methyl)-2-p-tolylH-imidazo[1,2-a]pyridine,N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-imidazol-2-amine,3-((5-methyl-1,3,4-thiadiazol-2-ylthio)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine,3-((1,3,4-thiadiazol-2-ylthio)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine,N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-pyrazol-5-amine,ethyl5-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methylamino)-1H-pyrazole-4-carboxylate,N-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-4-methylpyrimidin-2-amine,N-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-4,6-dimethylpyrimidin-2-amine,5-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methylamino)-1H-pyrazole-4-carbonitrile,N-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-4-methoxy-6-methylpyrimidin-2-amine,N-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-4,6-dimethoxypyrimidin-2-amine,N-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)benzo[c][1,2,5]thiadiazol-4-amine,6-methyl-3-((thiophen-2-ylthio)methyl)-2-p-tolylH-imidazo[1,2-a]pyridine,6-methyl-3-((pyridin-3-yloxy)methyl)-2-p-tolylH-imidazo[1,2-a]pyridine,N-((6,8-dichloro-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-4,6-dimethylpyrimidin-2-amine,N-((6,8-dichloro-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-imidazol-2-amine,3-((4,6-dimethylpyrimidin-2-ylthio)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine,3-((benzo[d]oxazol-2-ylthio)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine,N-((2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-4-methylpyrimidin-2-amine,N-((6-chloro-2-phenylH-imidazo[1,2-a]pyridin-3-yl)methyl)-4-methylpyrimidin-2-amine,4-methyl-N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)thiazol-2-amine,N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-triazin-3-amine,N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1,3,5-triazin-2-amine,and2-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methylamino)-3-methylisoquinolin-1(2H)-one.

In exemplary embodiments, the invention provides compounds having astructure set forth in Table 2:

TABLE 2

In various embodiments, the compounds of the invention are activeagainst one or more benzodiazepine receptor. In various embodiments ofthe invention, the compounds of the invention have activity versus thebenzodiazepine central and/or benzodiazepine peripheral receptor of atleast 40% inhibition at 10 μM. In certain embodiments, the compoundshave an activity versus the benzodiazepine central and/or benzodiazepineperipheral receptor with an IC₅₀ less than or equal to 1 μM. In variousembodiments, the compounds of the invention have an activity versus thebenzodiazepine central and/or benzodiazepine peripheral receptor with anIC₅₀ less than or equal to 0.3 μM. In certain embodiments the inventionprovides compounds having activity versus the benzodiazepine centraland/or benzodiazepine peripheral receptor with an IC₅₀ less than orequal to 0.1 μM.

In an exemplary embodiment, the invention provides compounds that aretwo-fold selective for the benzodiazepine central receptor over thebenzodiazepine peripheral receptor. In various embodiments compounds ofthe invention are ten-fold selective for the benzodiazepine centralreceptor over the benzodiazepine peripheral receptor. In certainembodiments, the compounds of the invention are 50-fold selective forthe benzodiazepine central receptor over the benzodiazepine peripheralreceptor. In an exemplary embodiment, compounds of the present inventioncan have similar activity, defined as less than two-fold difference,versus both the benzodiazepine central and peripheral receptors. Oneskilled in the art will recognize that subtypes contribute to theeffects of GABA-A modulators. Such that compounds favoring differentsubtypes can have different therapeutic effects. The magnitude ofmodulation, for example, partial modulators can influence the effects invivo. Modulation favoring alpha 1 relative to alpha2 and/or alpha 3 canhave sedative hypnotic effects (e.g., zolpedem, zaleplon). Compoundswith reduced selectivity of alpha 1 can express anxiolytic effects withless sedation. Compounds with selectivity for alpha 5 can havememory/cognition enhancing effects.

The present invention further provides pharmaceutical compositionscomprising as active agents, the compounds described herein.

As used herein a “pharmaceutical composition” refers to a preparation ofone or more of the compounds described herein, or physiologicallyacceptable salts or solvates (including hydrates) thereof, with otherchemical components such as physiologically suitable carriers andexcipients.

Pharmaceutical compositions containing compounds of Formulae I, II, III,IV and any compound described herein can be conveniently presented inunit dosage form and prepared by any of the methods well known in theart of pharmacy. Preferred unit dosage formulations are those containingan effective dose, or an appropriate fraction thereof, of the activeingredient, or a pharmaceutically acceptable salt thereof. The magnitudeof a prophylactic or therapeutic dose typically varies with the natureand severity of the condition to be treated and the route ofadministration. The dose, and perhaps the dose frequency, will also varyaccording to the age, body weight and response of the individualpatient. In general, a dose ranges from about 0.1 mg to about 7000 mg,for example, about 1 mg to about 100 mg, or about, about 25 mg to about50 mg, in single or divided doses. In some embodiments, a dose can rangefrom about 50 mg to about 500 mg, for example, about 100 mg to about 500mg in single or divided doses. The compounds of the invention can beprovided in unit dosage format. The doses of compounds of the inventioncan be administered 1, 2, 3, 4, 5, 6 or more times in a day. It may berecommended that children, patients over 65 years old, and those withimpaired renal or hepatic function, initially receive low doses and thatthe dosage is titrated based on individual responses and/or bloodlevels. It may be necessary to use dosages outside these ranges in somecases, as will be apparent to those in the art. Further, it is notedthat the clinician or treating physician knows how and when tointerrupt, adjust or terminate therapy in conjunction with individualpatient's response.

In one embodiment, the pharaceutical composition comprises a compoundacccording to formula I wherein Z is CH, D, Q is1-methyl-1,2,4-triazol-5-yl, R¹ and R² are H, D, R³ is F at position 6,R⁴ is F at position 4′, and R⁵ and R⁶ are H.

One aspect of the present invention relates to combination therapy. Thistype of therapy is advantageous because the co-administration of activeingredients achieves a therapeutic effect that is greater than thetherapeutic effect achieved by administration of only a singletherapeutic agent. In one embodiment, the co-administration of two ormore therapeutic agents achieves a synergistic effect, i.e., atherapeutic affect that is greater than the sum of the therapeuticeffects of the individual components of the combination. In anotherembodiment, the co-administration of two or more therapeutic agentsachieves an augmentation effect.

The active ingredients that comprise a combination therapy can beadministered together via a single dosage form or by separateadministration of each active agent. In certain embodiments, the firstand second therapeutic agents are administered in a single dosage form.The agents can be formulated into a single tablet, pill, capsule, orsolution for parenteral administration and the like.

Alternatively, the first therapeutic agent and the second therapeuticagents can be administered as separate compositions, e.g., as separatetablets or solutions. The first active agent can be administered at thesame time as the second active agent or the first active agent can beadministered intermittently with the second active agent. The length oftime between administration of the first and second therapeutic agentcan be adjusted to achieve the desired therapeutic effect. In certaininstances, the second therapeutic agent can be administered only a fewminutes (e.g., 1, 2, 5, 10, 30, or 60 min) after administration of thefirst therapeutic agent. Alternatively, the second therapeutic agent canbe administered several hours (e.g., 2, 4, 6, 10, 12, 24, or 36 hr)after administration of the first therapeutic agent. In certainembodiments, it can be advantageous to administer more than one dosageof the second therapeutic agent between administrations of the firsttherapeutic agent. For example, the second therapeutic agent can beadministered at 2 hours and then again at 10 hours followingadministration of the first therapeutic agent. Alternatively, it can beadvantageous to administer more than one dosage of the first therapeuticagent between administrations of the second therapeutic agent.Importantly, it is preferred that the therapeutic effects of each activeingredient overlap for at least a portion of the duration of eachtherapeutic agent so that the overall therapeutic effect of thecombination therapy is attributable in part to the combined orsynergistic effects of the combination therapy.

The dosage of the active agents will generally be dependent upon anumber of factors including pharmacodynamic characteristics of eachagent of the combination, mode and route of administration of activeagent(s), the health of the patient being treated, the extent oftreatment desired, the nature and kind of concurrent therapy, if any,and the frequency of treatment and the nature of the effect desired. Ingeneral, dosage ranges of the active agents often range from about 0.001to about 250 mg/kg body weight per day. For example, for a normal adulthaving a body weight of about 70 kg, a dosage in the range of from about0.1 to about 25 mg/kg body weight is typically preferred. However, somevariability in this general dosage range can be required depending uponthe age and weight of the subject being treated, the intended route ofadministration, the particular agent being administered and the like.Since two or more different active agents are being used together in acombination therapy, the potency of each agent and the interactiveeffects achieved using them together must be considered. Importantly,the determination of dosage ranges and optimal dosages for a particularmammal is also well within the ability of one of ordinary skill in theart having the benefit of the instant disclosure.

In certain embodiments, it can be advantageous for the pharmaceuticalcombination to have a relatively large amount of the first componentcompared to the second component. In certain instances, the ratio of thefirst active agent to second active agent is 30:1, 20:1, 15:1, 10:1,9:1, 8:1, 7:1, 6:1, or 5:1. In certain embodiments, it can be preferableto have a more equal distribution of pharmaceutical agents. In certaininstances, the ratio of the first active agent to the second activeagent is 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, or 1:4. In certain embodiments,it can be advantageous for the pharmaceutical combination to have arelatively large amount of the second component compared to the firstcomponent. In certain instances, the ratio of the second active agent tothe first active agent is 30:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, or5:1. Importantly, a composition comprising any of the above-identifiedcombinations of first therapeutic agent and second therapeutic agent canbe administered in divided doses 1, 2, 3, 4, 5, 6, or more times per dayor in a form that will provide a rate of release effective to attain thedesired results. In a preferred embodiment, the dosage form containsboth the first and second active agents. In a more preferred embodiment,the dosage form only has to be administered one time per day and thedosage form contains both the first and second active agents.

For example, a formulation intended for oral administration to humanscan contain from 0.1 mg to 5 g of the first therapeutic agent and 0.1 mgto 5 g of the second therapeutic agent, both of which are compoundedwith an appropriate and convenient amount of carrier material varyingfrom about 5 to about 95 percent of the total composition. Unit dosageswill generally contain between from about 0.5 mg to about 1500 mg of thefirst therapeutic agent and 0.5 mg to about 1500 mg of the secondtherapeutic agent. In a preferred embodiment, the dosage comprises 0.5mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg,300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg, etc., up to 1500 mgof the first therapeutic agent. In a preferred embodiment, the dosagecomprises 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg, etc., upto 1500 mg of the second therapeutic agent.

The optimal ratios of the first and second therapeutic agent can bedetermined by standard assays known in the art. For example, thephenyl-p-benzoquinone test can be used to establish analgesiceffectiveness. The phenyl-p-benzoquinone induced writhing test in mice(H. Blumberg et al., 1965, Proc. Soc. Exp. Med. 118:763-766) and knownmodifications thereof is a standard procedure which can be used fordetecting and comparing the analgesic activity of different classes ofanalgesic drugs with a good correlation with human analgesic activity.Data for the mouse, as presented in an isobologram, can be translated toother species where the orally effective analgesic dose of theindividual compounds are known or can be estimated. The method consistsof reading the percent ED50 dose for each dose ratio on the best fitregression analysis curve from the mouse isobologram, multiplying eachcomponent by its effective species dose, and then forming the ratio ofthe amount of COX-2 inhibitor and opioid analgesic. This basiccorrelation for analgesic properties enables estimation of the range ofhuman effectiveness (E. W. Pelikan, 1959, The Pharmacologist 1:73).Thus, application of an equieffective dose substitution model and acurvilinear regression analysis utilizing all the data for theindividual compounds and various dose ratios for the combinations can beused to establish the existence of unexpectedly enhanced analgesicactivity of combinations of active agents, i.e., the resulting activityis greater than the activity expected from the sum of the activities ofthe individual components.

The toxicity and therapeutic efficacy of such compounds can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., for determining the LD50 (the dose lethal to50% of the population) and the ED50 (the dose therapeutically effectivein 50% of the population). The dose ratio between toxic and therapeuticeffects is the therapeutic index and it can be expressed as the ratioLD50/ED50. Compounds which exhibit large therapeutic indices arepreferred. The data obtained from these cell culture assays and animalstudies can be used in formulating a range of dosage for use in humans.The dosage of such compounds lies preferably within a range ofcirculating concentrations that include the ED50 with little or notoxicity. The dosage can vary within this range depending upon thedosage form employed and the route of administration utilized. For anycompound used in the method of the invention, the therapeuticallyeffective dose can be estimated initially from cell culture assays. Adose can be formulated in animal models to achieve a circulating plasmaconcentration range that includes the IC50 (i.e., the concentration ofthe test compound which achieves a half-maximal inhibition of RTproduction from infected cells compared to untreated control asdetermined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma can bemeasured, for example, by high performance liquid chromatography (HPLC).

Synergism and Augmentation

The term “synergistic” refers to a combination which is more effectivethan the additive effects of any two or more single agents. Asynergistic effect permits the effective treatment of a disease usinglower amounts (doses) of either individual therapy. The lower dosesresult in lower toxicity without reduced efficacy. In addition, asynergistic effect can result in improved efficacy, e.g., improvedbinding activity. Finally, synergy can result in an improved avoidanceor reduction of disease as compared to any single therapy.

Combination therapy can allow for the use of lower doses of the firsttherapeutic or the second therapeutic agent (referred to as “apparentone-way synergy” herein), or lower doses of both therapeutic agents(referred to as “two-way synergy” herein) than would normally berequired when either drug is used alone.

In certain embodiments, the synergism exhibited between the secondtherapeutic agent and the first therapeutic agent is such that thedosage of the first therapeutic agent would be sub-therapeutic ifadministered without the dosage of the second therapeutic agent.Alternatively, the synergism exhibited between the second therapeuticagent and the first therapeutic agent is such that the dosage of thesecond therapeutic agent would be sub-therapeutic if administeredwithout the dosage of the first therapeutic agent.

The terms “augmentation” or “augment” refer to combination where one ofthe compounds increases or enhances therapeutic effects of anothercompound or compounds administered to a patient. In some instances,augmentation can result in improving the efficacy, tolerability, orsafety, or any combination thereof, of a particular therapy.

In certain embodiments, the present invention relates to apharmaceutical composition comprising a therapeutically effective doseof a first therapeutic agent together with a dose of a secondtherapeutic agent effective to augment the therapeutic effect of thefirst therapeutic agent. In other embodiments, the present inventionrelates to methods of augmenting the therapeutic effect in a patient ofa first therapeutic agent by administering the second therapeutic agentto the patient. In various embodiments, the present invention relates toa pharmaceutical composition comprising a therapeutically effective doseof a second therapeutic agent together with a dose of a firsttherapeutic agent effective to augment the therapeutic effect of thesecond therapeutic agent. In selected embodiments, the present inventionrelates to methods of augmenting the therapeutic effect in a patient ofa second therapeutic agent by administering the first therapeutic agentto the patient.

In certain preferred embodiments, the invention is directed in part tosynergistic combinations of the first therapeutic agent in an amountsufficient to render a therapeutic effect together with a secondtherapeutic agent. For example, in certain embodiments a therapeuticeffect is attained which is at least about 2 (or at least about 4, 6, 8,or 10) times greater than that obtained with the dose of the firsttherapeutic agent alone. In certain embodiments, the synergisticcombination provides a therapeutic effect which is up to about 20, 30 or40 times greater than that obtained with the dose of first therapeuticagent alone. In such embodiments, the synergistic combinations displaywhat is referred to herein as an “apparent one-way synergy”, meaningthat the dose of second therapeutic agent synergistically potentiatesthe effect of the first therapeutic agent, but the dose of firsttherapeutic agent does not appear to significantly potentiate the effectof the second therapeutic agent.

In certain embodiments, the combination of active agents exhibit two-waysynergism, meaning that the second therapeutic agent potentiates theeffect of the first therapeutic agent, and the first therapeutic agentpotentiates the effect of the second therapeutic agent. Thus, variousembodiments of the invention relate to combinations of a secondtherapeutic agent and a first therapeutic agent where the dose of eachdrug is reduced due to the synergism between the drugs, and thetherapeutic effect derived from the combination of drugs in reduceddoses is enhanced. The two-way synergism is not always readily apparentin actual dosages due to the potency ratio of the first therapeuticagent to the second therapeutic agent. For instance, two-way synergismcan be difficult to detect when one therapeutic agent displays muchgreater therapeutic potency relative to the other therapeutic agent.

The synergistic effects of combination therapy can be evaluated bybiological activity assays. For example, the therapeutic agents can bemixed at molar ratios designed to give approximately equipotenttherapeutic effects based on the EC90 values. Then, three differentmolar ratios are used for each combination to allow for variability inthe estimates of relative potency. These molar ratios are maintainedthroughout the dilution series. The corresponding monotherapies are alsoevaluated in parallel to the combination treatments using the standardprimary assay format. A comparison of the therapeutic effect of thecombination treatment to the therapeutic effect of the monotherapy givesa measure of the synergistic effect. Further details on the design ofcombination analyses can be found in B E Korba (1996) Antiviral Res.29:49. Analysis of synergism, additivity, or antagonism can bedetermined by analysis of the aforementioned data using the CalcuSyn™program (Biosoft, Inc.). This program evaluates drug interactions by useof the widely accepted method of Chou and Talalay combined with astatistically evaluation using the Monte Carlo statistical package. Thedata are displayed in several different formats including median-effectand dose-effects plots, isobolograms, and combination index [CI] plotswith standard deviations. For the latter analysis, a CI greater than 1.0indicates antagonism and a CI less than 1.0 indicates synergism.

Compositions of the invention present the opportunity for obtainingrelief from moderate to severe cases of disease. Due to the synergisticand/or additive effects provided by the inventive combination of thefirst and second therapeutic agent, it can be possible to use reduceddosages of each of therapeutic agent. By using lesser amounts of otheror both drugs, the side effects associated with each may be reduced innumber and degree. Moreover, the inventive combination avoids sideeffects to which some patients are particularly sensitive.

One aspect of the present invention relates to a pharmaceuticalcomposition of the present invention, or a pharmaceutically acceptablesalt, solvate, clathrate, polymorpH, D, or co-crystal thereof, and anantidepressant. Nonlimiting examples of antidepressants include withoutlimitation selective serotonin reuptake inhibitors, serotonin reuptakeinhibitors, norepinephrine reuptake inhibitors, dopamine reuptakeinhibitors, 5-HT 2A receptor modulators, triple reuptake inhibitors, anddouble reuptake inhibitors. In another aspect, the present inventiondiscloses a method of treating a patient suffering from a mooddiscorder, comprising the step of co-administering to a patient in needthereof a therapeutically effective amount of a compound of the presentinvention, or a pharmaceutically acceptable salt, and an antidepressant.

Nonlimiting examples of 5-HT 2A receptor modulators include MDL 100907,SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindolecompounds A, piperidinyl compounds B, spiroazacyclic compounds C, orazacyclic compounds D, or a pharmaceutically acceptable salt, clathrate,polymorpH, D, or co-crystal of any one of them.

Nonlimiting examples of serotonin reuptake inhibitors includecitalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine,milnacipran, paroxetine, sertraline, clominpramine, femoxetine,indapline, alaprolclate, cericlamine, or ifoxetine, or apharmaceutically acceptable salt, clathrate, polymorpH, D, or co-crystalof any one of them.

Nonlimiting examples of norepinephrine reuptake inhibitors includedesipramine, maprotiline, lofepramine, reboxetine, oxaprotiline,fezolamine, tomoxetine, or (S,S)-hydroxybupropion, or a pharmaceuticallyacceptable salt, clathrate, polymorpH, D, or co-crystal of any one ofthem.

Pharmaceutical compositions for use in accordance with the presentinvention can be formulated in a conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries, which facilitate processing of the active compounds intopreparations whicH, D, can be used pharmaceutically. The carriers mustbe acceptable in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof. Proper formulation is dependent upon the route ofadministration chosen. As will be understood by those of skill in theart, the carrier must be of a toxicity suitably low to be appropriatefor administeration to a subject.

Compounds that inhibit GABA can be formulated as pharmaceuticalcompositions and administered to a mammalian subject, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, i.e., orally, rectal, topical (including dermal, buccal,sublingual, and intraocular), or parenterally, by intravenous,intramuscular, topical, transdermal, intradermal, intraarticular, orsubcutaneous routes.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions, and the like, for oralingestion by a patient. Pharmacological preparations for oral use can bemade using a solid excipient, optionally grinding the resulting mixture,and processing the mixture of granules, after adding suitableauxiliaries if desired, to obtain tablets or dragee cores. Suitableexcipients are, in particular, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol; cellulose preparations such as,for example, maize starcH, D, wheat starcH, D, rice starcH, D, potatostarcH, D, gelatin, gum tragacantH, D, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carbomethylcellulose; and/orphysiologically acceptable polymers such as polyvinylpyrrolidone (PVP).If desired, disintegrating agents can be added, such as cross-linkedpolyvinyl pyrrolidone, agar or alginic acid or a salt thereof such assodium alginate.

In addition, an enteric coating may be useful as it is may be desirableto prevent exposure of the compounds of the invention to the gastricenvironment.

Pharmaceutical compositions, which can be used orally, include push-fitcapsules made of gelatin as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules may contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, lubricants such as talc ormagnesium stearate and, optionally, stabilizers. In soft capsules, theactive compounds can be dissolved or suspended in suitable liquids, suchas fatty oils, liquid paraffin, or liquid polyethylene glycols. Inaddition, stabilizers can be added.

Compositions for topical administration in the moutH, D, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavored basis such as sucrose and acacia or tragacantH,D, and pastilles comprising the active ingredient in a basis such asgelatin and glycerin or sucrose and acacia. All formulations for oraladministration should be in dosages suitable for the chosen route ofadministration.

For injection, the compounds of the invention can be formulated inaqueous solutions, preferably in physiologically compatible buffers suchas Hank's or Ringer's solution or physiological saline buffer. Fortransmucosal and transdermal administration, penetrants appropriate tothe barrier to be permeated can be used in the composition. Suchpenetrants, including for example DMSO or polyethylene glycol, are knownin the art.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from a pressurized pack or a nebulizer with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide. Inthe case of a pressurized aerosol, the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, e.g., gelatin for use in an inhaler or insufflator can be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

Pharmaceutical compositions for parenteral administration includeaqueous and non-aqueous sterile injection solutions, which can containanti-oxidants, buffers, bacteriostats and solutes, which render theformulation isotonic with the blood of the intended recipient.Compositions also include aqueous and non-aqueous sterile suspensions,which can include suspending agents and thickening agents.Pharmaceutical compositions for parenteral administration in an aqueoussolution contain the active ingredients in water-soluble form.Additionally, suspensions of the active compounds can be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidsesters such as ethyl oleate, triglycerides or liposomes. Aqueousinjection suspensions can contain substances, which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol or dextran. Optionally, the suspension can also containsuitable stabilizers or agents, which increase the solubility of thecompounds, to allow for the preparation of highly concentratedsolutions.

The formulations can be presented in unit-dose of multi-dose containers,for example sealed ampoules and vials, and can be stored in afreeze-dried (lyophilized) condition requiring only the addition of asterile liquid carrier, for example saline, phosphate-buffered saline(PBS) or the like, immediately prior to use. Extemporaneous injectionsolutions and suspensions can be prepared from sterile powders, granulesand tablets of the kind previously described.

The compounds of the present invention can also be formulated in rectalcompositions such as suppositories or retention enemas, using, e.g.,conventional suppository bases such as cocoa butter, polyethyleneglycol, or other glycerides.

Depending on the severity and responsiveness of the condition to betreated, dosing can also be a single administration of a slow releasecomposition, with course of treatment lasting from several days toseveral weeks or until cure is effected or diminution of the diseasestate is achieved. The amount of a composition to be administered will,of course, be dependent on many factors including the subject beingtreated, the severity of the affliction, the manner of administration,the judgment of the prescribing physician. The compounds of theinvention can be administered orally or via injection at a dose from0.001 to 250 mg/kg per day. The dose range for adult humans is generallyfrom 0.5 mg to 10 g/day. Tablets or other forms of presentation providedin discrete units can conveniently contain an amount of compound of theinvention which is effective at such dosage or as a multiple of thesame, for instance, units containing 5 mg to 500 mg, usually around 10mg to 200 mg. The precise amount of compound administered to a patientwill be the responsibility of the attendant physician. However, the doseemployed will depend on a number of factors, including the age and sexof the patient, the precise disorder being treated, and its severity.Also, the route of administration can vary depending on the conditionand its severity.

As used herein, and as would be understood by the person of skill in theart, the recitation of “a compound” is intended to include salts,solvates and inclusion complexes of that compound. The term “solvate”refers to a compound described herein and/or according to Formula I, II,III, or IV in the solid state, wherein molecules of a suitable solventare incorporated in the crystal lattice. A suitable solvent fortherapeutic administration is physiologically tolerable at the dosageadministered. Examples of suitable solvents for therapeuticadministration are ethanol and water. When water is the solvent, thesolvate is referred to as a hydrate. In general, solvates are formed bydissolving the compound in the appropriate solvent and isolating thesolvate by cooling or using an antisolvent. The solvate is typicallydried or azeotroped under ambient conditions. Inclusion complexes aredescribed in Remington: The Science and Practice of Pharmacy 19th Ed.(1995) volume 1, page 176-177, which is incorporated herein byreference. The most commonly employed inclusion complexes are those withcyclodextrins, and all cyclodextrin complexes, natural and synthetic,are specifically encompassed within the claims.

The term “pharmaceutically acceptable salt” refers to salts preparedfrom pharmaceutically acceptable non-toxic acids or bases includinginorganic acids and bases and organic acids and bases. When thecompounds of the present invention are basic, salts can be prepared frompharmaceutically acceptable non-toxic acids including inorganic andorganic acids. Suitable pharmaceutically acceptable acid addition saltsfor the compounds of the present invention include acetic,benzenesulfonic (besylate), benzoic, camphorsulfonic, citric,ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaricacid, p-toluenesulfonic, and the like. When the compounds contain anacidic side chain, suitable pharmaceutically acceptable base additionsalts for the compounds of the present invention include metallic saltsmade from aluminum, calcium, lithium, magnesium, potassium, sodium andzinc or organic salts made from lysine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of this invention can include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration caninclude flavoring agents.

The compositions can be presented in a packaging device or dispenser,which can contain one or more unit dosage forms containing the activeingredient. Examples of a packaging device include metal or plasticfoil, such as a blister pack and a nebulizer for inhalation. Thepackaging device or dispenser can be accompanied by instructions foradministration. Compositions comprising a compound of the presentinvention formulated in a compatible pharmaceutical carrier can also beplaced in an appropriate container and labeled for treatment of anindicated condition.

III. Chemical Synthesis

Terminology related to “protecting”, “deprotecting” and “protected”functionalities occurs throughout this application. Such terminology iswell understood by persons of skill in the art and is used in thecontext of processes that involve sequential treatment with a series ofreagents. In that context, a protecting group refers to a group used tomask a functionality during a process step in which it would otherwisereact, but in which reaction is undesirable. The protecting groupprevents reaction at that step, but may be subsequently removed toexpose the original functionality. The removal or “deprotection” occursafter the completion of the reaction or reactions in which thefunctionality would interfere. Thus, when a sequence of reagents isspecified, as it is in the processes of the invention, the person ofordinary skill can readily envision those groups that would be suitableas “protecting groups”. Suitable groups for that purpose are discussedin standard textbooks in the field of chemistry, such as ProtectiveGroups in Organic Synthesis by T. W. Greene [John Wiley & Sons, NewYork, 1991], which is incorporated herein by reference.

A comprehensive list of abbreviations utilized by organic chemistsappears in the first issue of each volume of the Journal of OrganicChemistry. The list, which is typically presented in a table entitled“Standard List of Abbreviations”, is incorporated herein by reference.

In general, the compounds of the present invention can be prepared bythe methods illustrated in the general reaction schemes as, for example,described below, or by modifications thereof, using readily availablestarting materials, reagents and conventional synthesis procedures. Inthese reactions, it is also possible to make use of variants that are inthemselves known, but are not mentioned here. The starting materials,for example in the case of suitably substituted benzimidazole ringcompounds, are either commercially available, synthesized as describedin the examples or can be obtained by the methods well known to personsof skill in the art.

Starting materials of structure type W, for some of the compounds of theinvention, are prepared as follows:

Some of the compounds of the invention are prepared according to MethodA (for the synthesis of Formulae II and IV)

Some of the compounds of the invention are prepared according to MethodB (for the synthesis of compounds of Formula III)

Some of the compounds of the invention are prepared according to MethodC (General procedure for nucleophilic addition to aldehyde anddehydroxylations (for the synthesis of formula IV where Y is nil)

Some of the compounds of the invention are prepared according to MethodD (Preparation of imidazopyridines with carbon-carbon bonded 6-memberedaromatic side chains, formula IV where Y is nil).

Other compounds of the invention not prepared by the above Methods aredescribed as appropriate in the corresponding sections.

IV. Indications

The compounds of the present invention are useful in modulating theactivity of GABA receptor complex or in modulating GABA mediatedactivity and are useful for treatment of and preventing central nervoussystem (CNS) disorders such as anxiety disorders (e.g., GAD and panicdisorder) and a number of conditions in which GABA is believed to exerta physiologic role. These conditions include psychiatric disorders,convulsive disorders, aggressive behavior disorders, muscle spasms ortensing, depressive or bipolar disorders, cognitive disorders, sleepingdisorders, neurodegenerative eye diseases, neurodegeneration, pain,emesis, or eating disorders and of complications arising therefrom.

The compounds described supra and to be described infra are useful intreating and/or preventing anxiety disorders, which can have theiretiology in both psychologic and physiologic factors. Emotional stresscan precipitate anxiety neurosis which represents the individual's fearof losing control of such emotional drives as aggressive or dependencyneeds, and losing control of his resulting actions. Physiologically,anxiety is associated with autonomic nervous system discharge and therelated neurohumoral processes. In acute anxiety attacks, lasting from afew minutes to an hour, the individual experiences a subjective sense ofterror, for no evident reason, and perhaps a haunting dread ofcatastrophe. Chronic anxiety displays less intense symptoms of longerduration, characterized by uneasiness, nervousness, nagging uncertaintyabout future events, headache, fatigue, and subacute autonomic symptoms.

Furthermore, the compounds described herein are useful in treatingand/or preventing psychotic disorders, which tend towards chronicity,which impair functioning, and which are characterized by psychoticsymptoms of disturbed thinking, feeding, and general behavior. Clear,goal-directed behavior becomes difficult, while blunting andinappropriate affect are the most characteristic emotional changes.Auditory hallucinations can be common, and delusions of persecution arefrequent, as are threats of violence, minor aggressive outbursts andaggressive behavior. Disturbances of movement can range from significantover activity and excitement to retardation and stupor. Treatment hasoften included tranquilizers with the pharmacologic profile of compoundsof the current invention, and other antipsychotic drugs, either orallyor by long-acting depot injection to offset problems of patientcompliance.

In addition, the compounds described herein are useful for treatingand/or preventing other disorders such as convulsive disorders likeepilepsy. Seizure disorders or epilepsy represent a broad group ofcentral nervous system disorders of function that are characterized byrecurrent, sudden, often brief attacks, which may alter consciousness,motor activity, sensory phenomena, and autonomic responses, and whichmay prompt inappropriate behavior. Recurrent seizure patterns of eitheran idiopathic or symptomatic etiology are termed epilepsy. The mostcommon form of these recurrent but transient episodes are convulsiveseizures, which may include loss of consciousness, motor function andcontrol, and which may produce tonic or clonic jerking of theextremities. Pharmacological treatment of epilepsy has been directed tocontrol based on seizure type, rather than etiology. Accordingly, theconvulsions have been grouped in broad, but rather distinct types,including Tonic-clonic (Grand Mal), Partial (Focal) seizures,psychomotor (Complex partial) seizures, pyknoepileptic or Absence (PetitMal) and the less frequent Myoclonic seizures.

The compounds described herein are also useful in the treatment and/orprevention of spasticity and acute muscle spasm. Spasticity representsnot a single disorder, but rather a range of abnormalities of regulationof skeletal muscle that result from problems at various levels of thecentral nervous system. A predominant component is heightened muscletone or hyper-excitability of tonic stretch muscle reflexes. While thepathopysiology of these disorders remains rather poorly understood, itoften includes dysfunction of the descending spinal pathways.Presynaptic inhibition of motorneurons, as may be induced by GABA, oragents that in some respects resemble and/or exhibit the pharmacology ofGABA provides some antispastic affect. Additionally, benzodiazepines, ordrugs like compounds of the present invention that bind to thebenzodiazepine receptor, can enhance the efficiency of inhibitoryGABA-ergic transmission, and thus can provide some efficacy in thetreatment or conditions of spasticity, particularly those due to spinalcord lesions. Acute muscle spasm can be associated with a variety ofconditions including trauma, inflammation, anxiety, and pain.

The compounds described herein are useful for the treatment and/orprevention of sleep disorders. Difficulties in falling asleep, remainingasleep, sleeping for adequate lengths of time, or abnormal sleepbehavior are common symptoms for those suffering with a sleep disorder.A number of sleep disorders, e.g., insomnia or sleep apnea, aredescribed in the online Merck Manual of Medical Information. Insomnia ischaracterized by difficulty in sleeping or disturbed sleep patterns.Insomnia can be of a primary nature with little apparent relationship tointermediate somatic or psychic events, or secondary to some acquiredpain, anxiety, or depression. Where possible, treatment is directed tothe underlying cause of the condition; hypnotic medication is generallyreserved for insomnia of emotional disturbances and for refractory casesdue to more common causes.

In exemplary embodiments, the invention provides a method for treatingor preventing a disease or condition selected from the group consistingof anxiety disorders; psychiatric disorders; convulsive disorders;aggressive behavior; muscle spasms or tension; depressive or bipolardisorders; cognitive disorders; sleeping disorders; neurodegenerativeeye diseases; neurodegeneration; pain; epilepsy; schizophrenia; emesisand eating disorders; comprising administering to a patient atherapeutically effective amount of one or more compounds of the presentinvention, or a pharmaceutically acceptable salt thereof.

The following examples will further describe the invention, and are usedfor purposes of illustration only, and should not be considered aslimiting the invention being disclosed. In general, the compounds of thepresent invention can be prepared by the methods illustrated in thereaction schemes as, for example, described below, or by modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. In these reactions, it is alsopossible to make use of variants that are in themselves known, but arenot mentioned here. Compounds of the invention can be synthesized asfollows.

The invention is illustrated by the following Examples, but is notlimited to the specific embodiments contained therein.

EXAMPLES

General Procedure: Flash chromatography was performed on EM Sciencesilica gel 60. Thin layer chromatography was performed using silica gel60 F₂₅₄ plates, and compound visualization was effected using a UV lightor with 10% H₂SO₄ containing 5% ammonium molybdate and 0.2% cericsulfate. ¹H Nuclear Magnetic Resonance (NMR) and ¹³C NMR spectroscopywere performed on a 400 MHz Varian instrument. Tetramethylsilane (TMS),deuterated chloroform (CDCl₃) or deuterated dimethyl sulfoxide (DMSO-d₆)were used as internal standards for ¹H, D and ¹³C spectra, respectively.J values are given in hertz.

Example 13-((1H-imidazol-1-yl)methyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine(1) Step 1: 6-Methyl-2-(4-methylphenyl)-imidazo[1,2-a]-pyridine

A mixture of 2-bromo-4′-methylacetophenone (90% pure, 10.21 g, 43.11mmol), 2-amino-5-methyl picoline (4.66 g, 43.11 mmol) and K₂CO₃ (6.6 g,47.75 mmol) in absolute EtOH (70 ml) was heated at 93° C. overnight.After cooled to 40° C., ether (100 mL) was added. The mixture wasstirred for 30 minutes and cooled by ice-water bath. After removal ofsolvent through filtration, the solid was stirred with water (50 ml) for30 minutes and filtered, rinsed with water and dried under vacuum at 80°C. for 2 hr to give 6.33 g of white solid (66.1% yield). m/e⁺ 223.4 forC₁₅H₁₅N₂ (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 7.84 (m, 3H), 7.71 (d,J=9.531 Hz, 1), 7.51 (d, J=9.165 Hz, 1H), 7.24 (m, 2H), 7.00 (m, 1),2.38 (s, 3H), 2.29 (d, J=6.23 Hz, 3H) ppm. ¹³C-NMR (100 MHz, CDCl₃ δ)145.065, 144.444, 137.991, 130.696, 130.635, 129.642, 129.483, 128.391,128.262, 126.018, 123.652, 122.476, 116.486, 107.857, 21.520, 18.259ppm.

Step 2: 6-Methyl-2-p-tolyl-H-imidazo[1,2-a]pyridine-3-carbaldehyde

DMF (50 ml) was cooled to 0° C. and phosphorus oxotrichloride (3.54 ml,38.6 mmol) was added dropwise. After addition, the mixture was warmed toroom temperature and stirred for 10 min. To this solution, the startingmaterial (6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine, 4.29 g, 19.32mmol) was added in a few portions. The resulting mixture was stirred atroom temperature until the reaction was complete as monitored by TLC andLC-mass analysis (18-24 hr). The reaction mixture was then poured intoice-cooled water (200 ml). The pH was adjusted to 7 with concentratedammonium hydroxide. The mixture was extracted with CH₂Cl₂ (2×100 ml).The combined organic solution was washed with brine and dried withNa₂SO₄. After removal of most of the solvent, ether was added toprecipitate out a white solid. The white solid was collected byfiltration. The mother liquid was concentrated and the white solid wascollected again. (3.89 g, 80.5%). m/e⁺ 251 for C₁₆H₁₅N₂O (M+H)⁺; ¹H-NMR(300 MHz, CDCl₃, δ) 10.025 (s, 1H), 9.48 (d, J=0.9 Hz, 1H), 7.72 (m,3H), 7.43 (dd, J₁=9.3 Hz, J₂=1.8 Hz, 1H), 7.32 (d, J=8.1 Hz, 2H), 2.441(s, 6H, D, 2×CH₃) ppm.

Step 3: (6-Methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methanol

To a suspension of6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine-3-carbaldehyde (1.50 g, 6.0mmol) in MeOH (30 ml) and THF (10 ml) at 0° C. was added NaBH₄ (265 mg,7.0 mmol). The mixture was stirred for 10 min and concentrated underreduced pressure to give a white solid, which was stirred with water (30ml) for 30 min and collected by filtration. After rinsed several timeswith water, the white solid was dried under vacuum. (1.47 g, 97.3%).m/e⁺ 253.5 for C₁₆H₁₇N₂O (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃-CD₃OD, δ) 7.989(s, 1H), 7.55 (d, J=8.1 Hz, 2H), 7.42 (d, J=9.3 Hz, 1H), 7.16 (d, J=8.10Hz, 2H), 7.05 (d, J=9.3 Hz, 1H), 5.01 (s, CH₂), 2.35 (s, 3H, D, CH₃),2.30 (s, 3H, D, CH₃) ppm; ¹³C-NMR (100 MHz, CDCl₃-CD₃OD, δ) 144.049,137.991, 130.893, 129.377, 128.876, 128.550, 122.552, 122.302, 115.887,53.519, 21.178, 18.183 ppm. Note: the compound is not very soluble inEtOAc, CH₂Cl₂, CHCl₃. It is soluble in MeOH.

Step 4: 3-(Chloromethyl)-6-methyl-2-p-tolyl-H-imidazo[1,2-a]pyridinehydrochloride

To a suspension of(6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methanol (1.47 g, 5.83mmol) in CH₂Cl₂ (15 ml) was at 0° C. was added thionyl chloride (SOCl₂,2.0 ml). The suspension became a clear solution. Then white solid wasformed again in the reaction solution. After stirred at 0° C. for 3 hrs,the reaction mixture was poured into ether (100 ml). The white solid wascollected by filtration and rinsed with ether and dried under reducedpressure. The product is not soluble in most organic solvents and isreactive towards nucleophilic solvents such as alcohols and water.However, it is stable in solid state and can be kept at room temperaturefor months without decomposition.

Step 5:3-((1H-imidazol-1-yl)methyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine

A mixture of 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridinehydrochloride (0.10 mmol), 1H-imidazole (0.20 mmol, 2.0 eq) in AcCN (1ml) was heated at 65° C. overnight. The mixture was basified with sat.NaHCO₃ (5 ml), extracted with ethyl acetate or CH₂Cl₂ (2×5 ml). Thecombined organic solution was dried with Na₂SO₄, evaporated undervacuum. The product was purified by silica gel column chromatography (12g silica gel RediSep column, eluted first with 10% ethyl acetate inhexane, then 20-50% acetone in hexane), to afford the product as a whitesolid. The product shows up as violet spot on TLC plate under UV light.m/e⁺ 303.4 for C₁₉H₁₉N₄ (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 7.60-7.50 (m,5H), 7.26 (d, J=8.065 Hz, 2H), 7.11 (m, 2H), 6.883 (s, 1H), 5.51 (s,2H), 2.39 (s, 3H), 2.285 (s, 3H) ppm; ¹³C-NMR (100 MHz, CDCl₃, δ),146.681, 144.944, 138.582, 136.512, 130.787, 130.484, 129.832, 128.937,128.330, 123.341, 120.710, 118.845, 117.396, 112.315, 40.969, 21.512,18.608 ppm.

Example 26-Methyl-3-((2-methyl-1H-imidazol-1-yl)methyl)-2-p-tolylH-imidazo[1,2-a]pyridine(2)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 2-methyl-1H-imidazole. 35% yield; m/e⁺ 317.4 for C₂₀H₂₁N₄ (M+H)⁺;¹H-NMR (400 MHz, CDCl₃, δ) 7.61 (d, J=9.16 Hz, 1H), 7.53 (d, J=8.064 Hz,2H), 7.46 (s, 1H), 7.25 (d, J=8.064 Hz, 2H), 7.13 (dd, J₁=9.164 Hz,J₂=1.466 Hz, 1H), 6.887 (s, 1H), 6.56 (d, J=1.466 Hz, 1H), 5.344 (s,2H), 2.481 (s, 3H), 2.299 (s, 3H), 1.248 (s, 3H) ppm.

Example 33-((4,5-Dichloro-1H-imidazol-1-yl)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine(3)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 4,5-dichloro-1H-imidazole m/e⁺ 371.2 (100%), 373.2 (65%) forC₁₉H₁₇Cl₂N₄ (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 7.618 (d, 1H), 7.53 (m,3H), 7.27 (d, J=7.698 Hz, 2H), 7.17 (d, J=8.432 Hz, 1H), 6.995 (s, 1H),5.393 (s, 2H, D, CH₂), 2.399 (s, 3H, D, CH₃), 2.337 (s, 3H, D, CH₃) ppm.

Example 43-((2-Ethyl-1H-imidazol-1-yl)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine(4)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 2-ethyl-1H-imidazole. m/e⁺ 3314 for C₂₁H₂₃N₄ (M+H)⁺; ¹H-NMR (400MHz, CDCl₃, δ) 7.59 (d, J=9.164 Hz, 1H), 7.48 (d, J=8.064 Hz, 2H), 7.457(s, 1H), 7.24 (d, J=8.065 Hz, 2H), 7.12 (d, J=9.163 Hz, 1H), 6.91 (d,J=5.132 Hz, 2H), 6.552 (s, 1H), 5.341 (s, 2H, D, CH₂), 2.76 (m, 2H, D,CH₂), 2.385 (s, 3H, D, CH₃), 2.285 (s, 3H, D, CH₃), 1.38 (t, 3H, D, CH₃)ppm.

Example 53-((2-Isopropyl-1H-imidazol-1-yl)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine(5)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 2-isopropyl-1H-imidazole. m/e⁺ 335.4 for C₂₂H₂₅N₄ (M+H)⁺; ¹H-NMR(400 MHz, CDCl₃, δ) 7.60 (d, J=9.531 Hz, 1H), 7.52 (d, J=8.065 Hz, 2H),7.469 (s, 1H), 7.24 (d, J=8.431 Hz, 1H), 7.14 (dd, J₁=9.165 Hz, J₂=1.467Hz, 1H), 6.92 (d, J=1.099 Hz, 1H), 6.51 (d, J=1.099 Hz), 5.376 (s, 2H,D, CH₂), 3.15 (m, 1H, D, CH), 2.392 (s, 3H, D, CH₃), 2.289 (s, 3H, D,CH₃), 1.40 (d, J=6.965 Hz, 6H, D, 2×CH₃) ppm.

Example 63-((1H-1,2,3-triazol-1-yl)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine(6)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 1H-1,2,3-triazole. m/e⁺ 304.5 for C₁₈H₁₈N₅ (M+H)⁺; ¹H-NMR (400 MHz,CDCl₃, δ) 7.81 (s, 1H), 7.66 (s, 1H), 7.59 (d, J=8.06 Hz, 2H), 7.55 (d,J=9.16 Hz, 1H), 7.37 (s, 1H), 7.27 (d, 8.06 Hz, 2H), 7.11 (dd, J₁=9.17Hz, J₂=1.1 Hz, 2H), 5.97 (s, 1H), 2.39 (s, 3H), 2.28 (s, 3H) ppm.

Example 73-((1H-1,2,4-triazol-1-yl)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine(7)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 1H-1,2,4-triazole in 48% yield; m/e⁺ 304.5 for (M+H)⁺; ¹H-NMR (400MHz, CDCl₃, δ) 7.99 (s, 1H), 7.94 (s, 1H), 7.85 (s, 1H), 7.57 (m, 3H),7.20 (d, J=7.70 Hz, 2H), 7.13 (d, J=9.16 Hz, 1H), 5.70 (s, 2H), 2.39 (s,3H), 2.31 (s, 3H) ppm.

Example 83-((1H-pyrazol-1-yl)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine(8)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 1H-pyrazole. m/e⁺ 303.4 for C₁₉H₁₉N₄ (M+H)⁺ 303.4; ¹H-NMR (400 MHz,CDCl₃, δ) 7.80 9 s, 1H), 7.64 (d, J=8.06 Hz, 2H), 7.59 (d, J=2.2 Hz,1H), 7.56 (s, 1H), 7.25 (m, 3H), 7.10 (dd, J₁=9.164, J₂=1.47 Hz, 1H),6.26 (m, 1H), 5.73 (s, 1H), 2.41 (s, 3H), 2.30 (s, 3H) ppm.

Example 96-Methyl-3-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-2-p-tolylH-imidazo[1,2-a]pyridine(9)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 3,5-dimethyl-1H-pyrazole. m/e⁺ 331.4 for C₂₁H₂₃N₄ (M+H)⁺, ¹H-NMR(400 MHz, CDCl₃, δ) 8.249 (s, 1H), 7.58 (d, J=7.698 Hz, 2H), 7.49 (d,J=9.165 Hz, 1H), 7.27 (d, J=8.064 Hz, 2H), 7.04 (dd, J₁=9.164 Hz,J₂=1.466 Hz, 1H), 5.692 (s, 1H), 5.635 (s, 2H, D, CH₂), 2.403 (s, 3H, D,CH₃), 0.2285 (s, 3H, D, CH₃), 2.201 (s, 3H, D, CH₃), 1.696 (s, 3H, D,CH₃) ppm.

Example 102-(6-Methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-ylmethyl)-2H-[1,2,4]triazole-3-carboxylicacid methyl ester (10) and Example 111-(6-Methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-ylmethyl)-1H-[1,2,4]triazole-3-carboxylicacid methyl ester (11)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand methyl 1H-1,2,4-triazole-5-carboxylate. The two isomers wereseparated by silica gel chromatography eluted with 20% acetone to flashout the less polar spot and 50% acetone to flash out the second spot(more polar spot). Compound 10: m/e⁺ 362 for C₂₀H₂₀N₅O₂ [M+H]⁺; ¹H-NMR(400 MHz, CDCl₃) δ 7.95 (s, 2H), 7.65 (d, J=8.0 Hz, 2H), 7.56 (d, J=9.1Hz, 1H), 7.23 (d, J=8.0 Hz, 2H), 7.10 (dd, J=1.4, 9.1 Hz, 1H), 6.15 (s,2H), 3.98 (s, 3H), 2.38 (s, 3H), 2.31 (s, 3H) ppm; Compound 11: m/e⁺ 362for C₂₀H₂₀N₅O₂ [M+H]⁺; ¹H-NMR (400 MHz, CDCl₃) δ 7.91 (s, 1H), 7.74 (s,1H), 7.58 (d, J=9.5 Hz, 1H), 7.54 (d, J=7.7 Hz, 2H), 7.24 (d, J=7.7 Hz,2H), 7.14 (d, J=9.5 Hz, 1H), 5.81 (s, 2H), 3.98 (s, 3H), 2.37 (s, 3H),2.29 (s, 3H) ppm.

Example 121-(6-Methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-ylmethyl)-1H-imidazole-2-carboxylicacid ethyl ester (12)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand ethyl 1H-imidazole-2-carboxylate. m/e⁺ 375 for C₂₂H₂₃N₄O₂ [M+H]⁺;¹H-NMR (300 MHz, CDCl₃) δ 7.63 (m, 4H), 7.24 (m, 4H), 6.73 (d, J=0.9 Hz,1H), 6.07 (s, 2H), 4.39 (m, 2H), 2.39 (s, 3H), 2.29 (s, 3H), 1.43 (m,3H) ppm.

Example 136-Methyl-3-((2-phenyl-1H-imidazol-1-yl)methyl)-2-p-tolylH-imidazo[1,2-a]pyridine(13)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 2-phenyl-1H-imidazole. m/e⁺ 379.4 for C₂₅H₂₃N₄ (M+H)⁺.

Example 142-Methyl-1-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-benzo[d]imidazole(14)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 2-methyl-1H-benzo[d]imidazole. m/e⁺ 367.4 for C₂₄H₂₃N₄ (M+H)⁺.

Example 151-((6-Methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-imidazo[4,5-b]pyridine(15)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 2-methyl-1H-imidazo[4,5-b]pyridine. m/e⁺ 354.4 for C₂₂H₂₀N₅ (M+H)⁺;¹H-NMR (400 MHz, CDCl₃, δ) 8.526 (dd, J₁=4.765 Hz, J₂=1.1 Hz, 1H), 8.10(dd, J₁=8.065 Hz, J₂=1.1 Hz, 1H), 7.900 (s, 1H), 7.716 (s, 1H), 7.67 (d,J=8.065 Hz, 2H), 7.58 (d, J=9.164 Hz, 1H), 7.31 (m, 2H), 7.10 (d,J₁=9.165 Hz, J₂=1.467 Hz, 1H), 5.90 (s, 2H), 2.416 (s, 3H, D, CH₃),2.223 (s, 3H, D, CH₃) ppm.

Example 161-((6-Methyl-2-p-tolyl-H-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-benzo[d]imidazole(16)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 1H-benzo[d]imidazole. m/e⁺ 353.4 for C₂₃H₂₁N₄ (M+H)⁺; ¹H-NMR (400MHz, CDCl₃, δ) 7.85-7.12 (m, 12H), 5.68 (s, 2H), 2.387 (s, 3H, D, CH₃),2.23 (s, 3H, D, CH₃) ppm.

Example 17

N,N-Dimethyl-9-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-9H-purin-6-amine(17)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand N,N-dimethyl-9H-purin-6-amine. m/e⁺ 398.4 for C₂₃H₂₄N₇ (M+H)⁺;¹H-NMR (400 MHz, CD₃OD, δ) 8. 453 (s, 1H), 7.956 (s, 1H), 7.66 (d,J=8.065 Hz, 2H), 7.56 (d, J=9.164 Hz, 1H), 7.368 (s, 1H), 7.28 (d,J=7.698 Hz, 2H), 7.07 (dd, J₁=9.164 Hz, J₂=1.466 Hz, 1H), 5.765 (s, 2H,D, CH₂), 3.51 (broad, 6H, D, 2×CH₃), 2.414 (s, 3H, D, CH₃), 2.239 (s,3H, D, CH₃) ppm.

Example 183-((1H-1,2,4-triazol-1-yl)methyl)-6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridine(18)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride and 1H-1,2,4-triazole. m/e⁺ 344.3 (100%), 346.3 (60%),345.3 9 (20%), 347.2 9 (10%) for C₁₆H₁₂Cl₂N₅(M+H)⁺; ¹H-NMR (400 MHz,CDCl₃, δ) 8.31 (s, 1H), 8.058 (s, 1H), 8.004 (s, 1H), 7.62 (m, 3H), 7.46(dd, J₁=9.531 Hz, J₂=0.733 Hz, 1H), 7.44 (dd, J₁=6.598 Hz, J₂=1.832 Hz,2H), 7.26 (dd, J₁=6.598 Hz, J₂=1.833 Hz, 2H), 7.27 (d, J=9.531 Hz, 1H),5.685 (s, 2H, D, CH₂) ppm.

Example 193-((1H-1,2,3-triazol-1-yl)methyl)-6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridine(19)

The title compound was prepared according to Method A and theexperimentals described for compound 2 from6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride and 1H-1,2,3-triazole. m/e⁺ 344.3 (100%), 346.3 (60%) forC₁₆H₁₂Cl₂N₅ (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 8.23 (d, J=1.1 Hz, 1H),7.74 (d, J=1.1 Hz, 1H), (s, 1H), 7.65 (m, 3H), 7.45 (m, 3H), 7.30 (d,J=7.698 Hz, 1H), 5.965 (s, 2H, D, CH₂) ppm.

Example 20 Methyl1-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate(20) and Example 21 Methyl2-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-2H-1,2,4-triazole-3-carboxylate(21)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride and methyl 1H-1,2,4-triazole-5-carboxylate. The twoisomers were separated by silica gel chromatography (eluted with 20%acetone/hexane to flush out the less polar isomer and then flashed with50% acetone to get the second compound off the column. Compound 20: m/e⁺402.3 (100%), 404.2 (65%) for C₁₈H₁₄Cl₂N₅O₂ (M+H)⁺; ¹H-NMR (300 MHz,CDCl₃, δ), 8.41 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.81 (d, 2H), 7.77 (d,J=9.3 Hz, 1H), 7.48 (d, 2H), 7.30 (d, 1H), 6.21 (s, 2H), 4.07 (s, 3H)ppm. Compound 21: m/e⁺ 402.3 (100%), 404.2 (65%) for C₁₈H₁₄Cl₂N₅O₂(M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 8.37 (d, J=1.1 Hz, 1H), 8.00 (s, 1H),7.76 (dd, J₁=6.598 Hz, J₂=1.833 Hz, 2H), 7.62 (dd, J₁=9.531 Hz, J₂=0.733Hz, 1H), 7.44 (dd, J₁=6.598 Hz, J₂=1.832 Hz, 2H), 7.26 (dd, J₁=9.531 Hz,J₂=1.833 Hz, 1H), 6.18 (s, 2H, D, CH₂), 4.035 (s, 3H, D, CH₃) ppm.¹³C-NMR (100 MHz, CDCl₃, δ) 159.025, 151.670, 146.916, 144.345, 144.201,135.033, 131.94, 130.256, 129.953, 129.187, 127.451, 122.385, 121.604,118.329, 114.272, 53.769, 44.245 ppm.

Example 221-[6-Chloro-2-(4-chloro-phenyl)-imidazo[1,2-a]pyridin-3-ylmethyl]-1H-imidazole-2-carboxylicacid ethyl ester (22)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride and ethyl 1H-imidazole-2-carboxylate. m/e⁺ 416 forC₂₀H₁₇Cl₂N₄O₂ [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ 8.04 (dd, J=0.9, 6.3 Hz,1H), 7.60 (m, 3H), 7.42 (dd, J=6.3, 8.1 Hz, 2H), 7.27 (m, 1H), 7.11 (m,1H), 6.67 (dd, J=2.1, 3.3 Hz, 1H), 6.07 (d, J=2.1 Hz, 2H), 4.48 (q,J=7.2 Hz, 2H), 1.48 (t, J=7.2 Hz, 3H) ppm; ¹³C-NMR (75 MHz, CDCl₃, δ)160.222, 135.309, 130.815, 130.735, 129.653, 129.593, 127.897, 123.336,123.283, 122.261, 121.647, 121.573, 118.475, 62.384, 53.016, 41.598,41.544, 14.534 ppm.

Example 232-[6-Chloro-2-(4-chloro-phenyl)-imidazo[1,2-a]pyridin-3-ylmethyl]-2H-[1,2,4]triazole-3-carboxylicacid isopropyl ester (23)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride and isopropyl 1H-1,2,4-triazole-5-carboxylate. m/e⁺ 430for C₂₀H₁₈Cl₂N₅O₂ [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ 8.41 (dd, J=0.9, 1.8Hz, 1H), 8.01 (s, 1H), 7.82 (dd, J=2.1, 6.6 Hz, 2H), 7.64 (dd, J=0.9,9.3 Hz, 1H), 7.46 (dd, J=2.1, 6.6 Hz, 2H), 7.28 (dd, J=1.8, 9.3 Hz, 1H),6.21 (s, 2H), 5.38 (m, 1H), 1.50 (d, J=6.0 Hz, 6H) ppm; ¹³C-NMR (75 MHz,CDCl₃, δ) 158.353, 151.649, 146.894, 144.844, 144.190, 135.015, 132.017,130.301, 129.199, 127.410, 122.448, 121.573, 118.355, 114.495, 71.973,44.202, 21.946 ppm.

Example 242-[2-(4-Chloro-phenyl)-imidazo[1,2-a]pyridin-3-ylmethyl]-2H-[1,2,4]triazole-3-carboxylicacid methyl ester (24) and Example 251-[2-(4-Chloro-phenyl)-imidazo[1,2-a]pyridin-3-ylmethyl]-1H-[1,2,4]triazole-3-carboxylicacid methyl ester (25)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand methyl 1H-1,2,4-triazole-3-carboxylate. The two isomers wereseparated by silica gel chromatography (eluted with 20% acetone/hexaneto flush out the less polar isomer and then flashed with 50% acetone toget the second compound off the column. Compound 24: m/e⁺ 368 forC₁₈H₁₅ClN₅O₂ [M+H]⁺; ¹H-NMR (400 MHz, CDCl₃) δ 8.24 (d, J=6.6 Hz, 1H),7.95 (s, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.65 (d, J=9.1 Hz, 1H), 7.42 (d,J=8.8 Hz, 2H), 7.27 (m, 1H), 6.86 (m, 1H), 6.19 (s, 2H), 4.00 (s, 3H)ppm; Compound 25: m/e⁺ 368 for C₁₈H₁₅ClN₅O₂ [M+H]⁺; ¹H-NMR (400 MHz,CDCl₃) δ 8.06 (d, J=6.6 Hz, 1H), 8.00 (s, 1H), 7.62 (m, 3H), 7.44 (m,2H), 7.29 (m, 1H), 6.89 (d, J=5.8 Hz, 1H), 5.83 (s, 2H), 3.95 (s, 3H)ppm.

Example 26 Ethyl1-((2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-imidazole-2-carboxylate(26)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and ethyl1H-imidazole-2-carboxylate. m/e+ 375 for C22H23N4O2 [M+H]+; 1H-NMR (300MHz, CDCl3 7.90 (d, J=6.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.63 (d,J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.30 (t, J=7.2 Hz, 1H), 7.08 (s,1H), 6.86 (t, J=6.8 Hz, 1H), 6.66 (s, 1H), 6.10 (s, 2H), 4.51 (q, J=6.8Hz, 2H), 1.47 (t, J=6.8 Hz, 3H) ppm; m/e 381.

Example 272-(4-chlorophenyl)-3-((2-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-imidazol-1-yl)methyl)H-imidazo[1,2-a]pyridine(27)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand 5-(1H-imidazol-2-yl)-3-methyl-1,2,4-oxadiazole and5-(1H-imidazol-2-yl)-3-methyl-1,2,4-oxadiazole. ¹H-NMR (CDCl₃, 400 MHz,δ) 7.87 (d, J=6.4 mg, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.68 (d, J=10 Hz,2H), 7.44 (t, J=1.6 Hz, 1H), 7.33 (m, 2H), 6.88 (t, J=6.8 Hz, 1H), 6.20(s, 2H), 2.52 (s, 3H) ppm;

Example 28 Ethyl1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-3-methyl-1H-pyrazole-5-carboxylate(28) and Example 29 ethyl1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-5-methyl-1H-pyrazole-3-carboxylate(29)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand ethyl 3-methyl-1H-pyrazole-5-carboxylate. The regioisomers wereseparated by silica gel chromatography. Compound 28: M/e⁺ 395 forC₂₁H₂₀ClN₄O₂ (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃) δ 8 24 (d, J=6.9 Hz, 1H),7.82 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.8 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H),7.17 (td, J=6.6, 1.1 Hz, 1H), 6.78 (td, J=6.6, 1.1 Hz, 1H), 6.50 (s,1H), 6.01 (s, 2H), 4.30 (q, J=7.3 Hz, 2H), 2.26 (s, 3H), 1.30 (q, J=7.3Hz, 3H) ppm; Compound 29: M/e⁺ 395 for C₂₁H₂₀ClN₄O₂ (M+H)⁺; ¹H-NMR (400MHz, CDCl₃) δ 8.47 (d, J=6.6 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.63 (m,1H), 7.48 (d, J=8.4 Hz, 2H), 7.24 (t, J=6.6 Hz, 1H), 6.84 (t, J=6.6 Hz,1H), 6.44 (s, 1H), 5.84 (s, 2H), 4.36 (q, J=7.3 Hz, 2H), 1.73 (s, 3H),1.37 (t, J=3H) ppm.

Example 30 Ethyl1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylate(30) and Example 31 Ethyl1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-3-(furan-2-yl)-1H-pyrazole-5-carboxylate(31)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand ethyl 5-(furan-2-yl)-1H-pyrazole-3-carboxylate. The regioisomerswere separated silica gel chromatogrpahy. Compound 30: M/e⁺ 447 forC₂₄H₂₀ClN₄O₃ (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃) δ 8 7.93 (d, J=6.2 Hz, 1H),7.67 (d, J=7.7 Hz, 2H), 7.56 (d, J=9.1 Hz, 1H), 7.34 (d, J=7.7 Hz, 2H),7.25 (d, J=2.9 Hz, 1H), 7.17 (m, 1H), 6.98 (s, 1H), 6.81 (t, J=6.6 Hz,1H), 6.62 (s, 1H), 6.09 (s, 1H), 4.40 (m, 4H), 1.39 (t, J=6.9 Hz, 3H)ppm; Compound 31: M/e⁺ 447 for C₂₄H₂₀ClN₄O₃ (M+H)⁺; ¹H-NMR (400 MHz,CDCl₃) δ 8 37 (d, J=6.9 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.65 (d, J=9.1Hz, 1H), 7.42 (m, 3H), 7.24 (m, 1H), 7.09 (s, 1H), 6.84 (td, J=6.6, 1.1Hz, 1H), 6.58 (d, J=3.3 Hz, 1H), 6.40 (dd, J=3.3, 1.8 Hz, 1H), 6.15 (s,2H), 4.36 (q, J=7.3 Hz, 2H), 1.39 (t, J=7.3 Hz, 3H) ppm.

Example 33-((1H-1,2,4-triazol-1-yl)methyl)-2-(4-chlorophenyl)imidazo[1,2-b]pyridazine(32)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand 1H-1,2,4-triazole. ¹H-NMR (CDCl₃, 400 MHz, δ) 8.74 (s, 1H) 8.07 (d,J=8.5 Hz, 2H), 8.07 (d, J=8.5 Hz, 2H), 8.01 (dd, J=1.3, 9.2 Hz, 1H),7.95 (s, 1H), 7.51 (m, 2H), 7.17 (dd, J=4.5, 9.2 Hz, 1H), 5.85 (s, 2H)ppm; [M+H]+311

Example 33 Methyl4-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4H-furo[3,2-b]pyrrole-5-carboxylate(33)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloridemethyl 4H-furo[3,2-b]pyrrole-5-carboxylate. M/e⁺ 406 for C₂₂H₁₇ClN₃O₃(M+H)⁺; ¹H-NMR (400 MHz, CDCl₃) δ 9.18 (s, 1H), 7.95 (d, J=7.71 Hz, 1H),7.71 (d, J=8.4 Hz, 2H), 7.63 (t, J=8.8 Hz, 1H), 7.39 (d, J=8.4 Hz, 2H),7.22 (m, 2H), 6.82 (t, J=6.6 Hz, 1H), 5.98 (s, 1H), 4.45 (s, 2H), 3.83(s, 3H) ppm.

Example 34 Methyl1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-indazole-3-carboxylate(34)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloridemethyl 1H-indazole-3-carboxylate. M/e⁺ 417 for C₂₃H₁₈ClN₄O₂ (M+H)⁺;¹H-NMR (400 MHz, CDCl₃) δ 8.22 (d, J=6.9 Hz, 1H), 8.03 (d, J=6.6 Hz,1H), 7.83 (d, J=8.4 Hz, 2H), 7.68 (dd, J=8.8, 1.8 Hz, 2H), 7.41 (d,J=8.4 Hz, 2H), 7.30 (m, 2H), 7.24 (m, 1H), 6.81 (t, J=6.2 Hz, 1H), 6.47(s, 2H), 4.03 (s, 3H) ppm.

Example 35 Methyl1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)indoline-2-carboxylate(35)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand methyl indoline-2-carboxylate. M/e⁺ 418 for C₂₄H₂₁ClN₃O₂ (M+H)⁺;¹H-NMR (400 MHz, CDCl₃) δ 8.33 (d, J=6.9 Hz, 1H), 7.69 (d, J=8.4 Hz,2H), 7.64 (d, J=9.1 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.25 (t, J=6.9 Hz,1H), 7.09 (t, J=7.7 Hz, 1H), 7.04 (d, J=6.9 Hz, 1H), 6.83 (t, J=6.6 Hz,1H), 6.75 (t, J=7.7 Hz, 1H), 6.60 (d, J=7.7 Hz, 1H), 4.90 (d, J=14.7 Hz,1H), 4.62 (d, J=14.7 Hz, 1H), 3.85 (t, J=8.4 Hz, 1H), 3.26 (m, 1H), 3.23(s, 3H), 2.96 (dd, J=15.7, 8.0 Hz, 1H) ppm.

Example 361-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N-methyl-1H-benzo[d]imidazole-2-carboxamide(36)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand N-methyl-1H-benzo[d]imidazole-2-carboxamide. M/e⁺ 416 forC₂₃H₁₉ClN₅O (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃) δ 8.40 (d, J=6.9 Hz, 1H),7.90 (d, J=4.7 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.62 (dd, J=13.1, 8.0Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.18 (dd, J=8.4, 1.1 Hz, 2H), 6.98 (m,1H), 6.73 (m, 1H), 6.67 (s, 2H) 3.12 (d, J=5.1 Hz, 3H) 1.83 (s, 1H) ppm.

Example 37 Ethyl1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-indole-2-carboxylate(37)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand ethyl 1H-indole-2-carboxylate. M/e⁺ 430 for C₂₅H₂₁ClN₃O₂ (M+H)⁺;¹H-NMR (400 MHz, CD₃OD) δ 8.13 (d, J=6.6 Hz, 1H), 7.70 (dd, J=8.4, 2.2Hz, 2H), 7.55 (d, J=9.1 Hz, 1H), 7.42 (d, J=8.4, 2.5 Hz, 2H), 7.33 (d,J=8.4 Hz, 1H), 7.25 (t, J=6.6 Hz, 1H), 7.10 (t, J=6.6 Hz, 1H), 6.79 (m,1H), 6.67 (m, 1H), 6.61 (m, 2H), 5.03 (s, 2H), 4.44 (q, J=6.9 Hz, 2H),1.39 (t, J=6.9 Hz, 3H) ppm.

Example 38

Methyl1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-indole-3-carboxylate(38)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand methyl 1H-indole-3-carboxylate. M/e⁺ 430 for C₂₅H₂₁ClN₃O₂ (M+H)⁺;¹H-NMR (400 MHz, CDCl₃) δ 8.24 (dd, J=5.8, 2.5 Hz, 1H), 7.74 (d, J=9.1Hz, 2H), 7.66 (d, J=8.4 Hz, 1H), 7.64 (m, 1H), 7.51 (s, 1H), 7.48 (m,1H), 7.42 (d, J=8.4 Hz, 2H), 7.31 (m, 2H), 7.29 (t, J=5.8 Hz, 1H), 6.80(t, J=6.9 Hz, 1H), 5.67 (s, 2H), 3.83 (s, 3H) ppm.

Example 392-(4-Chloro-phenyl)-3-[1,2,3]triazol-2-ylmethyl-imidazo[1,2-a]pyridine(39) and Example 402-(4-Chloro-phenyl)-3-[1,2,3]triazol-1-ylmethyl-imidazo[1,2-a]pyridine(40)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand 1H-1,2,3-triazole. The two isomers were separated by silica gelchromatography (eluted with 20% acetone/hexane to flush out the lesspolar isomer and then flashed with 50% acetone to get the secondcompound off the column. Compound 39: m/e⁺ 310 for C₁₆H₁₃ClN₅ [M+H]⁺;¹H-NMR (400 MHz, CDCl₃) δ 8.55 (d, J=6.9 Hz, 1H), 8.06 (d, J=8.4 Hz,2H), 7.66 (t, J=5.1 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.28 (m, 1H), 7.26(s, 1H), 6.91 (m, 1H), 5.97 (s, 2H) ppm. Compound 40: m/e⁺ 310 forC₁₆H₁₃ClN₅ [M+H]⁺; ¹H-NMR (400 MHz, CDCl₃) δ 8.12 (d, J=6.6 Hz, 1H),7.70 (m, 4H), 7.48 (d, J=8.8 Hz, 2H), 7.41 (d, J=0.7 Hz, 1H), 7.31 (m,1H), 6.89 (dt, J=1.1, 6.6 Hz, 1H), 6.01 (s, 2H) ppm.

Example 413-((1H-tetrazol-1-yl)methyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine(41)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand 1H-tetrazole. M/e⁺ 311 for C₁₅H₁₂ClN₆ (M+H)⁺; ¹H-NMR (400 MHz,CDCl₃) δ 8.45 (s, 1H), 8.12 (d, J=6.9 Hz, 1H), 7.73 (d, J=9.1 Hz, 1H),7.64 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 7.37 (td, J=6.9, 1.1 Hz,1H), 6.97 (m, 1H), 6.03 (s, 2H) ppm.

Example 421-((2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-benzo[d][1,2,3]triazole(42) and Example 432-((2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-2H-benzo[d][1,2,3]triazole(43)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand 1H-benzo[d][1,2,3]triazole. The two regioisomers were separated bysilica gel chromatography. Compound 42: ¹H-NMR (CDCl₃, 400 MHz, δ) 8.29(d, J=6.9 Hz, 1H), 7.97 (m, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.61 (d, J=9.1Hz, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.25 (m, 3H), 6.81 (m, 2H), 6.26 (s,2H) ppm; [M+H]+360; Compound 43: ¹H-NMR (CDCl₃, 400 MHz, δ) 8.65 (d,J=6.9 Hz, 1H), 8.15 (d, J=8.5 Hz, 2H), 7.88 (m, 2H), 7.69 (d, J=9.1 Hz,1H), 7.54 (d, J=8.5 Hz, 2H), 7.43 (m, 2), 7.30 (m, 1H), 6.94 (m, 1H),6.25 (s, 2H) ppm; [M+H]+360.

Example 442-(6-Chloro-2-phenyl-imidazo[1,2-a]pyridin-3-ylmethyl)-2H-[1,2,4]triazole-3-carboxylicacid methyl ester (44) and Example 451-(6-Chloro-2-phenyl-imidazo[1,2-a]pyridin-3-ylmethyl)-1H-[1,2,4]triazole-3-carboxylicacid methyl ester (45)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from6-chloro-3-(chloromethyl)-2-phenylimidazo[1,2-a]pyridine hydrochlorideand methyl 1H-1,2,4-triazole-3-carboxylate. The two isomers wereseparated by silica gel chromatography (eluted with 20% acetone/hexaneto flush out the less polar isomer (44) and then flashed with 50%acetone to get the second compound off the column (45). Compound 44:m/e⁺ 368 for C₁₈H₁₅ClN₅O₂ [M+H]⁺; ¹H-NMR (400 MHz, CDCl₃) δ 8.35 (d,J=1.1 Hz, 1H), 7.98 (s, 1H), 7.76 (dd, J=1.4, 8.0 Hz, 2H), 7.61 (d,J=9.5 Hz, 1H), 7.42 (m, 3H), 7.24 (m, 1H), 6.17 (s, 2H), 3.97 (s, 3H)ppm; Compound 45: m/e⁺ 368 for C₁₈H₁₅ClN₅O₂ [M+H]⁺; ¹H-NMR (400 MHz,CDCl₃) δ 8.18 (d, J=1.1 Hz, 1H), 7.99 (s, 1H), 7.63 (m, 3H), 7.44 (m,3H), 7.25 (m, 1H), 5.82 (s, 2H), 3.97 (s, 3H) ppm.

Example 461-((6-chloro-2-phenylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-benzo[d][1,2,3]triazole(46) and Example 472-((6-chloro-2-phenylH-imidazo[1,2-a]pyridin-3-yl)methyl)-2H-benzo[d][1,2,3]triazole(47)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from6-chloro-3-(chloromethyl)-2-phenylimidazo[1,2-a]pyridine hydrochlorideand 1H-benzo[d][1,2,3]triazole. The two regioisomers were separated bysilica gel chromatography. Compound 46:1 H-NMR (CDCl₃, 400 MHz, δ) 8.42(d, J=1.3 Hz, 1H), 7.97 (d, J=7.3 Hz, 1H), 7.52 (m, 4H), 7.24 (m, 2H),7.17 (dd, J=1.9, 9.5 Hz, 1H), 6.98 (dd, J=4.6, −147.3 Hz, 1H), 6.23 (s,2H) ppm; [M+H]+360; Compound 47: ¹H-NMR (CDCl₃, 400 MHz, δ) 8.74 (s,1H), 8.13 (d, J=7.2 Hz, 2H), 7.91 (m, 2H), 7.63 (d, J=9.5 Hz, 1H), 7.57(m, 2H), 7.48 (d, J=7.4 Hz, 1H), 7.41 (m, 2H), 7.26 (dd, J=7.4 Hz, 1H),6.25 (s, 2H) ppm; [M+H]+360.

Example 483-((1H-1,2,3-triazol-1-yl)methyl)-2-(4-fluorophenyl)H-imidazo[1,2-a]pyridine(48) and Example 493-((2H-1,2,3-triazol-2-yl)methyl)-2-(4-fluorophenyl)H-imidazo[1,2-a]pyridine(49)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-fluorophenyl)imidazo[1,2-a]pyridine hydrochlorideand 1H-1,2,3-triazole. The two regioisomrs were separated bychromatohraphy. Compound 48: ¹H-NMR (CDCl₃, 400 MHz, δ) 8.51 (d, J=6.9Hz, 1H), 7.7 (m, 3H), 7.39 (s, 1H), 7.30 (m, 2H), 7.20 (t, J=8.5 Hz,2H), 6.88 (t, J=6.8 Hz, 1H), 6.0 (s, 2H) ppm; m/e 294 (M+H)⁺; Compound49: ¹H-NMR (CDCl₃, 400 MHz, δ) 8.52 (d, J=6.8 Hz, 1H), 8.07 (t, J=6.4Hz, 2H), 7.63 (m, 3H), 7.22 (m, 3H), 6.88 (m, 1H), 5.90 (s, 2H) ppm; m/e294 (M+H)⁺

Example 503-((1H-1,2,3-triazol-1-yl)methyl)-2-phenylH-imidazo[1,2-a]pyridine (50)and Example 513-((2H-1,2,3-triazol-2-yl)methyl)-2-phenylH-imidazo[1,2-a]pyridine (51)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-phenylimidazo[1,2-a]pyridine hydrochloride and1H-1,2,3-triazole. The two regioisomrs were separated by chromatohraphy.Compound 50: ¹H-NMR (CDCl₃, 400 MHz, δ) 8.11 (d, J=6.9 Hz, 1H), 7.74 (d,J=7.1 Hz, 2H), 7.70 (d, J=6.5 Hz, 2H), 7.51 (t, J=7.4 Hz, 2H), 7.46 (d,J=7.3 Hz, 1H), 7.40 (s, 1H), 7.30 (t, J=7.9 Hz, 1H), 6.87 (t, J=6.4 Hz,1H), 6.03 (s, 2H) ppm. m/e 276 (M+H)⁺; Compound 51: ¹H-NMR (CDCl₃, 400MHz, δ) 8.1 (d, J=6.9 Hz, 1H), 8.08 (d, J=7.3 Hz, 2H), 7.65 (m, 3H),7.51 9 m, 2H), 7.41 (m, 1H), 8.07 (t, J=6.4 Hz, 1H), 6.86 (t, J=6.8 Hz,1H), 6.0 (s, 2H) ppm. m/e 276 (M+H)⁺.

Example 52 Methyl1-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate(52) and Example 53 Methyl1-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylate(53)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridinehydrochloride and methyl 1H-1,2,4-triazole-5-carboxylate. The twoisomers were separated by silica gel chromatography eluted with 20%acetone to flash out the less polar spot and 50% acetone to flash outthe second spot (more polar spot). m/e⁺ 370 for C18H14F2N5O2 (M+H)⁺.

Example 543-((1H-1,2,4-triazol-1-yl)methyl)-2-(4-fluorophenyl)H-imidazo[1,2-a]pyridine(54)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from2-(4-fluorophenyl)-3-(chloromethyl)imidazo[1,2-a]pyridine hydrochlorideand 1H-1,2,4-triazole. ¹H-NMR (CDCl₃, 400 MHz, δ) 8.20 (dd, J=10.4, 11.7Hz, 1H), 8.09 (s, 1H), 7.96 (dd, J=10.3, 25.7 Hz, 2H), 7.68 (m, 3H),7.30 (t, J=7.9 Hz, 1H), 7.17 (m, 2H), 5.72 (s, 2H) ppm; m/e 294 (M+H)⁺

Example 553-((1H-1,2,4-triazol-1-yl)methyl)-2-(4-chlorophenyl)-6-fluoroH-imidazo[1,2-a]pyridine(55)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridinehydrochloride and 1H-1,2,4-triazole. ¹H-NMR (CDCl₃, 400 MHz, δ) 8.23 (t,J=3.1 Hz, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.64 (m, 3H), 7.46 (d, J=8.5Hz, 2H), 7.23 (m, 1H), 5.68 (s, 2H) ppm, [M+H]+312.

Example 563-((2H-1,2,3-triazol-2-yl)methyl)-2-(4-chlorophenyl)-6-fluoroH-imidazo[1,2-a]pyridine(56) and Example 573-((1H-1,2,3-triazol-1-yl)methyl)-2-(4-chlorophenyl)-6-fluoroH-imidazo[1,2-a]pyridine(57)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridinehydrochloride and 1H-1,2,3-triazole. The two regioisomers were separatedby silica gel chromatography. Compound 56: ¹H-NMR (CDCl₃, 400 MHz, δ)8.56 (dd, J=2.3, 4.0 Hz, 1H), 8.03 (d, J=8.5 Hz, 2H), 7.68 (s, 1H), 7.63(dd, J=5.1, 9.8 Hz, 1H), 7.51 (d, J=8.5 Hz, 2H), 7.20 (m, 1H), 5.93 (s,2H) ppm; [M+H]+328; Compound 57: ¹H-NMR (CDCl₃, 400 MHz, δ) 8.19 (m,1H), 7.64 (d, J=67.0 Hz, 1H), 7.65 (m, 2H), 7.51 (m 1H), 7.48 (m, 1H),7.44 (m, 1H), 7.22 (m, 1H), 5.96 (s, 2H) ppm; m/e 328, 330.

Example 581-((2-(4-chlorophenyl)-6-fluoroH-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-benzo[d][1,2,3]triazole(58) and Example 592-((2-(4-chlorophenyl)-6-fluoroH-imidazo[1,2-a]pyridin-3-yl)methyl)-2H-benzo[d][1,2,3]triazole(59)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridinehydrochloride and 1H-benzo[d][1,2,3]triazole. The two regioisomers wereseparated by silica gel chromatography. Compound 58:1 H-NMR (CDCl₃, 400MHz, δ) 8.30 (m, 1H), 7.99 (m, 2H), 7.71 (d, J=8.5 Hz, 2H), 7.59 (dd,J=5.0, 9.8 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.28 (m, 2H), 7.16 (m, 1H),6.86 (m, 1H), 6.20 (s, 2H) ppm; [M+H]+378; Compound 59:1 H-NMR (CDCl₃,400 MHz, δ) 8.69 (m, 1H), 8.12 (d, J=8.5 Hz, 2H), 7.90 (m, 2H), 7.64(dd, J=5.1, 9.8 Hz, 1H), 7.55 (d, J=−8.5 Hz, 2H), 7.40 (m, 2H), 7.22 (m,1H), 6.21 (s, 2H); [M+H]+378, 380.

Example 603-((2H-1,2,3-triazol-2-yl)methyl)-6-fluoro-2-(4-fluorophenyl)H-imidazo[1,2-a]pyridine(60) and Example 613-((1H-1,2,3-triazol-1-yl)methyl)-6-fluoro-2-(4-fluorophenyl)H-imidazo[1,2-a]pyridine(61)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridinehydrochloride and 1H-1,2,3-triazole. The two regioisomers were separatedby silica gel chromatography. Compound 60: ¹H-NMR (CDCl₃, 400 MHZ, δ)8.54 (dd, J=2.4, 3.9 Hz, 1H), 8.04 (m, 2H), 7.66 (s, 1H), 7.60 (dd,J=5.1, 9.9 Hz, 1H), 7.20 (m, 3H), 5.91 (s, 2H) ppm; [M+H]⁺ 312; Compound61: ¹H-NMR (CDCl₃, 400 MHz, δ) 8.14 (m, 1H), 7.2 (m, 2H), 7.65 (m, 1H),7.44 (s, 1H), 7.21 (m, 3H), 5.98 (s, 2H) ppm, {M+H]⁺ 312.

Example 623-((1H-1,2,4-triazol-1-yl)methyl)-6-chloro-2-(4-fluorophenyl)H-imidazo[1,2-a]pyridine(62)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from6-chloro-3-(chloromethyl)-2-(4-fluorophenyl)imidazo[1,2-a]pyridinehydrochloride and 1H-1,2,3-triazole. ¹H-NMR (CDCl₃, 400 MHz, δ) 8.30 (d,J=1.2 Hz, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.66 (m, 3H), 7.60 (d, J=9.6Hz, 1), 7.26 (dd, J=2 Hz, 10 Hz, 1H), 7.17 (m, 2H), 5.67 (s, 2H) ppm;[M+H]+328.

Example 633-((1H-1,2,4-triazol-1-yl)methyl)-2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridine(63)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridinehydrochloride and 1H-1,2,3-triazole. ¹H-NMR (CDCl₃, 400 MHz, δ) 7.92 (d,J=4.4 Hz, 1H), 7.80 (s, 1H), 7.63 (m, 2H), 7.48 (d, J=9.2 Hz, 1H), 7.09(m, 3H), 5.62 (s, 2H), 2.24 (s, 3H) ppm; [M+H]+308.

Example 643-((1H-1,2,4-triazol-1-yl)methyl)-2-(4-bromophenyl)H-imidazo[1,2-a]pyridine(64)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from2-(4-bromophenyl)-3-(chloromethyl)imidazo[1,2-a]pyridine hydrochlorideand 1H-1,2,4-triazole. ¹H-NMR (CDCl₃, 400 MHz, δ) 8.16 (d, J=6.9 Hz,1H), 8.1 (s, 1H), 7.99 (d, J=11.8 Hz, 2H), 7.67 (m, 3H), 7.30 (t, J=7.9Hz, 1H), 7.17 (m, 1H), 6.91 (m, 1H), 5.72 (s, 2H) ppm; m/e 355 (M+H)⁺

Example 653-((1H-pyrazol-1-yl)methyl)-6,8-dichloro-2-p-tolylimidazo[1,2-a]pyridine(65)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from6,8-dichloro-3-(chloromethyl)-2-p-tolylimidazo[1,2-a]pyridinehydrochloride and 1H-pyrazole. m/e⁺ 357 for C₁₈H₁₅Cl₂N₄ [M+H]⁺; ¹H-NMR(300 MHz, CDCl₃) δ 8.28 (d, J=2.1 Hz, 1H), 7.67 (d, J=7.8 Hz, 2H), 7.60(d, J=1.5 Hz, 1H), 7.35 (d, J=7.8 Hz, 2H), 7.30 (m, 2H), 6.31 (t, J=2.7Hz, 1H), 5.71 (s, 2H), 2.44 (s, 3H) ppm.

Example 666-Chloro-2-phenyl-3-[1,2,3]triazol-1-ylmethyl-imidazo[1,2-a]pyridine(66)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from2-(biphenyl-4-yl)-6-chloro-3-(chloromethyl)imidazo[1,2-a]pyridinehydrochloride and 1H-1,2,3-triazole. (m, 3H), 7.62 (dd, J=0.7, 9.5 Hz,1H), 7.52 (m, 2H), 7.46 (m, 2H), 7.26 (m, 1H), 5.99 (s, 2H) ppm.

Example 673-((1H-1,2,4-triazol-1-yl)methyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine(67)

The title compound was prepared according to Method A and theexperimentals described for compound 1 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-b]pyridazinehydrochloride and 1H-1,2,3-triazole. ¹H-NMR (400 MHz, CDCl₃, δ) 8.17 (d,J=6.8 Hz, 1H), 8.00 (s, 1H), 7.68 (m, 3H), 7.52 (m, 2H), 7.33 (m, 1H),7.26 (m, 1H), 6.93 (m, 1H), 5.74 (s, 2H) ppm; m/e 310.

Example 682-(6-Methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-ylmethyl)-2H-[1,2,4]triazole-3-carboxylicacid methylamide (68)

Methyl1-((6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylatewas treated with excess methylamine in methanol in a sealed tube at 80°C. for several hours until the reaction was completed as judged by TLCor LC analysis. Solvent was evaporated and the crude product waspurified by chromatography (SiO₂ column, eluted with 50% acetone). m/e⁺361 for C₂₀H₂₁N₆O [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ 8.13 (d, J=0.6 Hz,1H), 7.87 (d, J=8.1 Hz, 2H), 7.65 (s, 1H), 7.57 (d, J=9.3 Hz, 1H), 7.27(d, J=8.1 Hz, 2H), 7.08 (dd, J=1.2, 9.3 Hz, 1H), 6.32 (s, 2H), 3.06 (d,J=5.1 Hz, 3H), 2.50 (bs, 1H), 2.41 (s, 3H), 2.31 (s, 3H) ppm; ¹³C-NMR(75 MHz, CDCl₃, δ) 158.440, 150.38, 146.788, 146.587, 138.174, 131.289,129.586, 129.413, 128.819, 128.612, 122.655, 122.094, 117.100, 113.447,44.395, 26.393, 21.605, 18.714 ppm.

Example 692-(6-Methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-ylmethyl)-2H-[1,2,4]triazole-3-carboxylicacid amide (69)

The title compound was prepared according to the procedure described forcompound 68 from methyl1-((6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylateand ammonia. m/e⁺ 347 for C₁₉H₁₉N₆O [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ8.10 (s, 1H), 7.87 (d, J=6.9 Hz, 2H), 7.61 (d, J=9.3 Hz, 1H), 7.41 (d,J=9.3 Hz, 1H), 7.30 (d, J=6.9 Hz, 2H), 7.12 (dd, J=1.2, 9.3 Hz, 1H),6.32 (s, 2H), 6.03 (bs, 2H), 2.43 (s, 3H), 2.34 (s, 3H) ppm.

Example 702-(6-Methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-ylmethyl)-2H-[1,2,4]triazole-3-carboxylicacid dimethylamide (70)

The title compound was prepared according to the procedure described forcompound 68 from methyl1-((6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylateand dimethylamine. m/e⁺ 375 for C₂₁H₂₃N₆O [M+H]⁺; ¹H-NMR (300 MHz,CDCl₃) δ 8.35 (s, 2H), 7.87 (d, J=2.1 Hz, 1H), 7.72 (d, J=7.8 Hz, 2H),7.54 (d, J=9.0 Hz, 1H), 7.26 (d, J=7.8 Hz, 2H), 7.10 (d, J=9.0 Hz, 1H),6.00 (s, 1H), 3.06 (s, 3H), 3.00 (s, 3H), 2.40 (s, 3H), 2.35 (s, 3H)ppm; ¹³C-NMR (75 MHz, CDCl₃, δ) 158.440, 150.213, 147.869, 146.313,144.771, 138.154, 131.236, 131.236, 129.600, 128.812, 128.725, 122.609,116.939, 113.480, 43.481, 38.888, 35.781, 21.585, 18.727 ppm.

Example 71N,N-Dimethyl-1-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-imidazole-2-carboxamide(71)

The title compound was prepared according to Method A and theexperimentals described for compound 68 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand N,N-dimethyl-1H-imidazole-2-carboxamide. The reagentN,N-dimethyl-1H-imidazole-2-carboxamide was prepared from the treatmentof 1H-imidazole-2-carboxylic acid with thionyl chloride followed by thereaction of the resulting 1H-imidazole-2-carbonyl chloride with dimethylamine in CH₂Cl₂. m/e⁺ 374.2 for C₂₂H₂₄N₅O (M+H)⁺; ¹H-NMR (400 MHz,CDCl₃, δ) 8.131 (s, 1H), 7.60 (d, J=7.698 Hz, 2H), 7.53 (d, J=9.165 Hz,1H), 7.24 (d, J=8.064 Hz, 2H), 7.07 (dd, J₁=9.164 Hz, J₂=1.1 Hz, 1H),6.944 (s, 1H), 6.635 (s, 1H), 5.924 (s, 2H, D, CH₂), 3.399 (s, 3H, D,CH₃), 3.146 (s, 3H, D, CH₃), 2.409 (s, 3H, D, CH₃), 2.37 (s, 3H, D, CH3)ppm; ¹³C-NMR (100 MHz, CDCl₃, δ) 161.399, 146.066, 144.861, 139.818,138.370, 131.030, 129.794, 129.028, 128.361, 128.254, 123.053, 122.310,120.967, 116.895, 113.680, 40.840, 39.680, 36.162, 21.520, 18.638 ppm.

Example 721-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxamide(72)

The title compound was prepared according to the procedure described forcompound 68 from methyl1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylateand ammonia. ¹H-NMR (D6-DMSO, 400 MHZ, d) 8.60 (d, J=6.9 Hz, 1H), 8.41(s, 1H), 8.17 (s, 1H), 8.03 (s, 1H), 7.83 (d, J=8.5 Hz, 2H), 7.65 (d,J=9.1 Hz, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.35 (t, J=7.9 Hz, 1H), 7.00 (t,J=6.8 Hz, 1H), 6.32 (s, 2H) ppm; m/e 353, 355.

Example 731-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N-methyl-1H-1,2,4-triazole-3-carboxamide(73)

The title compound was prepared according to the procedure described forcompound 68 from methyl1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylateand methylamine. ¹H-NMR (400 MHz, CDCl₃, δ) 8.42 (d, J=6.8 Hz, 1H), 7.98(d, J=8.5 Hz, 2H), 7.85 (s, 1H), 7.69 (d, J=9.1 Hz, 1H), 7.50 (broad,1H), 7.45 (d, J=8.5 Hz, 2H), 7.29 (m, 1H), 6.87 (m, 1H), 6.34 (s, 2H),3.08 (d, J=5.1 Hz, 3H) ppm; m/e 367, 369.

Example 741-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N,N-dimethyl-1H-1,2,4-triazole-5-carboxamide(74)

The title compound was prepared according to the procedure described forcompound 68 from methyl1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylateand dimethylamine. ¹H-NMR (400 MHz, CDCl₃, δ) 8.21 (d, J=6.9 Hz, 1H),7.97 (s, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.68 (d, J=8.5 Hz, 2H), 7.49 (d,J=8.4 Hz, 1H), 7.34 (m, 1H), 6.94 (m, 1H), 5.80 (s, 2H), 3.21 (s, 3H),3.13 (s, 3H) ppm; m/e 241, 243.

Example 751-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N,N-dimethyl-1H-1,2,4-triazole-3-carboxamide(75)

The title compound was prepared according to the procedure described forcompound 68 from methyl1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylateand dimthylamine. ¹H-NMR (400 MHz, CDCl₃, δ) 8.65 (d, J=6.9 Hz, 1H),7.88 (s, 1H), 7.85 (d, J=8.5 Hz, 2H), 7.66 (d, J=9.1 Hz, 1H), 7.45 (d,J=8.5 Hz, 2H), 7.28 (m, 1H), 6.89 (m, 1H), 6.04 (s, 2H), 3.15 (s, 3H),3.06 (s, 3H) ppm; m/e 381, 383.

Example 761-((2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-imidazole-2-carboxamide(76)

The title compound was prepared according to the procedure described forcompound 68 from methyl1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-imidazole-2-carboxylateand ammonia. ¹H-NMR (300 MHz, CDCl₃) 8.10 (d, J=6.9 Hz, 1H), 7.70 (d,J=8.4 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 7.36 (broad, 1H), 7.29 (t, J=7.9Hz, 1H), 6.96 (s, 1H), 6.85 (t, J=6.8 Hz, 1H), 6.63 (s, 1H), 6.27 (s,2H). m/e 352.

Example 771-((2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-N-methyl-1H-imidazole-2-carboxamide(77)

The title compound was prepared according to the procedure described forcompound 68 from methyl1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-imidazole-2-carboxylateand methylamine. ¹H-NMR (400 MHz, CDCl₃) 8.15 (d, J=6.9 Hz, 1H), 7.69(m, 2H), 7.47 (m, 2H), 7.25 (m, 1H), 6.91 (s, 1H), 6.85 (m, 1H), 6.60(s, 1H), 6.30 (s, 2H), 3.49 (s, 2H), 3.04 (d, J=5.1 Hz, 3H) ppm; m/e366, 368.

Example 781-((2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-1H-imidazole-2-carboxamide(78)

The title compound was prepared according to the procedure described forcompound 68 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand N1,N1-dimethylethane-1,2-diamine. H-NMR (CDCl₃, 400 MHz, δ) 8.11 (d,J=6.8 Hz, 1H), 7.82 (t, J=4.8 Hz, 1H), 7.65 (m, 2H), 7.42 (m, 2H), 7.24(m, 1H), 6.89 (s, 1H), 6.89 (m, 1H), 6.55 (s, 1H), 6.24 (s, 2H), 3.5 (m,2H), 3.25 (broad, 1H), 2.54 (m, 2H), 2.27 (s, 6H) ppm; m/e 423 (M+H)⁺

Example 791-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N,3-dimethyl-1H-pyrazole-5-carboxamide(79)

The title compound was prepared according to the procedure described forcompound 68 from 3 methyl1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-3-methyl-1H-pyrazole-5-carboxylateand methylamine. M/e⁺ 380 for C₂₀H₁₉ClN₅O (M+H)⁺; ¹H-NMR (400 MHz,CDCl₃) δ 8.29 (d, J=6.6 Hz, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.8Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.23 (m, 1H), 6.82 (t, J=6.9 Hz, 1H),6.66 (s, 1H), 6.05 (s, 2H), 3.84 (s, 3H), 2.19 (s, 3H) 1.57 (s, 1H),ppm;

Example 801-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N,5-dimethyl-1H-pyrazole-3-carboxamide(80)

The title compound was prepared according to the procedure described forcompound 68 from methyl1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-5-methyl-1H-pyrazole-3-carboxylateand methylamine. M/e⁺ 381 for C₂₀H₁₉ClN₅O (M+H)⁺; ¹H-NMR (400 MHz,CDCl₃) δ 8.20 (d, J=6.9 Hz, 1H), 7.68 m, 1H), 7.65 (d, J=8.4 Hz, 2H),7.47 (d, J=8.4 Hz, 2H), 7.28 (m, 1H), 6.86 (td, J=6.9, 1.1 Hz, 1H), 6.62(m, 1H), 6.52 (s, 1H), 5.64 (s, 2H), 2.93 (d, J=5.1 Hz, 3H), 1.99 (s,3H) ppm.

Example 812-[6-Chloro-2-(4-chloro-phenyl)-imidazo[1,2-a]pyridin-3-ylmethyl]-2H-[1,2,4]triazole-3-carboxylicacid methylamide (81)

The title compound was prepared according to the procedure described forcompound 68 from ethyl1-((6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-myl)methyl)-1H-1,2,4-triazole-5-carboxylateand methylamine. m/e⁺ 401 for C₁₈H₁₅Cl₂N₆O [M+H]⁺; ¹H-NMR (400 MHz,CDCl₃) δ 8.55 (s, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.86 (s, 1H), 7.60 (d,J=9.5 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.45 (s, 1H), 6.31 (s, 2H), 3.08(s, 3H) 1.20 (bs, 1H) ppm.

Example 822-[6-Chloro-2-(4-chloro-phenyl)-imidazo[1,2-a]pyridin-3-ylmethyl]-2H-[1,2,4]triazole-3-carboxylicacid methoxy-methyl-amide (82)

The title compound was prepared according to the procedure described forcompound 68 from1-((6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N-methoxy-N-methyl-1H-1,2,4-triazole-5-carboxamideand methoxymethanamine. m/e⁺ 431 for C₁₉H₁₇Cl₂N₆O₂ [M+H]⁺; ¹H-NMR (300MHz, CDCl₃) δ 8.90 (s, 1H), 7.74 (m, 3H), 7.51 (m, 4H), 6.02 (s, 2H),3.33 (s, 3H), 3.20 (s, 3H) ppm.

Example 831-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxamide(83)

The title compound was prepared according to the procedure described forcompound 68 from methyl1-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylateand ammonia. m/e+355 for C17H13F2N6O (M+H)+.

Example 841-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxamide(84)

The title compound was prepared according to the procedure described forcompound 68 from methyl1-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylateand ammonia. m/e+355 for C17H13F2N6O (M+H)+.

Example 851-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N-methyl-1H-1,2,4-triazole-5-carboxamide(85)

The title compound was prepared according to the procedure described forcompound 68 from methyl1-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylateand methylamine. m/e+368 for C18H15F2N6O (M+H)+.

Example 861-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carbohydrazide(86)

The title compound was prepared according to the procedure described forcompound 68 from methyl1-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylateand hydrazine hydrate. m/e+370 for C17H14F2N7O (M+H)+.

Example 871-((2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1H-imidazole-2-carboxamide(87)

The title compound was prepared according to the procedure described forcompound 68 from methyl1-((2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1H-imidazole-2-carboxylateand ammonia. ¹H-NMR (CDCl₃, 400 MHz, δ) 8.59 (d, J=4.4 Hz, 1H), 8.23 (d,J=9.2 Hz, 1H), 7.87 (s, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.57 (s, 1H), 7.50(d, J=8.4 Hz, 2H), 7.36 (dd, J=4.4, 9.2 Hz, 1H), 6.87 (s, 1H), 6.21 (s,2H) ppm; m/e 353 (M+H)⁺.

Example 881-((2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-N-methyl-1H-imidazole-2-carboxamide(88)

The title compound was prepared according to the procedure described forcompound 68 from methyl1-((2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1H-imidazole-2-carboxylateand methylamine ¹H-NMR (CDCl₃, 400 MHz, δ) 8.54 (d, J=4.4 Hz, 1H), 8.09(d, J=9.3 Hz, 1H), 7.87 (s, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.51 (s, 1H),7.47 (d, J=7.9 Hz, 2H), 7.37 (dd, J=4.5, 9.2 Hz, 1H), 6.93 (s, 1H), 6.90(s, 1H), 6.31 (s, 2H), 2.91 (s, 3H) ppm; m/e 367 (M+H)⁺.

Example 891-((2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxamide(89)

The title compound was prepared according to the procedure described forcompound 68 from methyl1-((2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylateand ammonia. ¹H-NMR (CDCl₃, 400 MHz, δ) 8.74 (s, 1H), 8.56 (dd, J=1.4,4.5 Hz, 1H), 8.08 (dd, J=1.5, 9.3 Hz, 1H), 8.02 (d, J=8.5 Hz, 2H), 7.57(d, J=8.5 Hz, 2H), 7.37 (dd, J=4.5, 9.2 Hz, 1H), 6.01 (s, 2H) ppm; m/e354 (M+H)⁺.

Example 901-((2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-N-methyl-1H-1,2,4-triazole-5-carboxamide(90)

The title compound was prepared according to the procedure described forcompound 68 from methyl1-((2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylateand methylamine. ¹H-NMR (CDCl₃, 400 MHz, δ) 8.42 (dd, J=1.5, 4.4 Hz,1H), 8.31 (s, 1H), 8.04 (dd, J=1.5, 9.2 Hz, 1H), 7.95 (d, J=8.5 Hz, 2H),7.52 (d, J=8.5 Hz, 2H), 7.20 (dd, J=4.5, 9.2 Hz, 1H), 7.06 (broad, 1H),5.91 (s, 2H), 3.00 (d, J=5.1 Hz, 3H)ppm; m/e 368 (M+H)⁺.

General Procedure for Imidazopyridinylmethyllactams (Formula III, MethodB from 1 d)

A mixture of 3-(chloromethyl)-imidazo[1,2-a]pyridine HCl salt (0.20mmol), hydroxylaromatics (0.41 mmol, 2.0 eq) or lactams (1-2 mmol, 5-10eq), K₂CO₃ (115 mg, 0.83 mmol, 4 eq) or NaH (10-20 eq) in AcCN or DMF (2ml) was heated at 65° C. or at room temperature until the reaction wascomplete. The mixture was treated with sat. NaHCO₃ (5 ml), extractedwith ethyl acetate or CH₂Cl₂ (2×10 ml). The combined organic solutionwas dried with Na₂SO₄, evaporated under vacuum. The product was purifiedby silica gel column chromatography (12 g silica gel RediSep column,eluted first with 10% ethyl acetate in hexane, then 20% acetone inhexane. The product shows up as violet spot on TLC plate under UV light.

Example 911,2-dihydro-3-methyl-1-((6-methyl-2-p-tolyl-H-imidazo[1,2-a]pyridin-3-yl)methyl)pyrazol-5-one(91)

A mixture of 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridinehydrochloride (0.20 mmol), 5-methyl-1H-pyrazol-3(2H)-one (2 mmol, 10 eq)K₂CO₃ (115 mg, 0.83 mmol, 4 eq) in AcCN (2 ml) was heated at 65° C.12-36 hr. The mixture was treated with sat. NaHCO₃ (5 ml), extractedwith ethyl acetate or CH₂Cl₂ (2×10 ml). The combined organic solutionwas dried with Na₂SO₄, evaporated under vacuum. The product was purifiedby silica gel column chromatography (12 g silica gel RediSep column,eluted first with 10% ethyl acetate in hexane, then 20% acetone inhexane. The product shows up as violet spot on TLC plate under UV light.m/e⁺ 333.4 for C₂₀H₂₁N₄O (M+H)⁺, ¹H-NMR (400 MHz, CDCl₃, δ) 8.211 (s,1H), 7.97 (d, J=7.698 Hz, 2H), 7.53 (d, J=9.165 Hz, 1H), 7.28 (d,J=7.698 Hz, 2H), 7.07 (d, J=8.798 Hz, 1H), 5.156 (s, 2H, D, CH₂), 2.406(s, 3H, D, CH₃), 2.347 (s, 3H, D, CH₃), 2.067 (s, 3H, D, CH₃) ppm.

Example 921-methyl-3-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)imidazolidin-2-one(92)

To a mixture of3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride(0.20 mmol), 1-methylimidazolidin-2-one (10 eq) in DMF (4 ml) at 0° C.was added NaH (20 eq). The reaction was exothermic, and gas was evolved.The mixture was stirred at room temperature over night. The reaction wasquenched by addition of water after the reaction was complete as judgedby LC-Mass analysis. The mixture was extracted with ethyl acetate (2×10ml). The combined organic solution was washed with brine and dried withNa₂SO₄, evaporated under vacuum. The product was purified by silica gelcolumn chromatography (12 g silica gel RediSep column, eluted first with10% ethyl acetate in hexane, then 20% acetone in hexane and finallyflashed with 50% acetone in hexane if necessary to get the product outoff the column. The product shows up as violet spot on TLC plate underUV light. m/e⁺ 335.4 for C₂₀H₂₃N₄O (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ)8.149 (s, 1H), 7.61 (d, J=7.699 Hz, 2H), 7.52 (d, J=8.798 Hz, 1H), 7.25(d, J=8.064 Hz, 2H), 7.07 (d, J=9.164 Hz, 1H), 4.857 (s, 2H), 3.18 (m,2H), 3.02 (m, 2H), 2.814 (s, 3H, D, CH₃), 2.398 (s, 3H, D, CH₃), 2.347(s, 3H, D, CH₃) ppm; ¹³C-NMR (100 MHz, CDCl₃, δ) 161.535, 145.414,144.444, 137.809, 131.735, 129.513, 128.702, 128.308, 122.810, 122.310,116.767, 115.205, 45.079, 42.4768, 38.080, 31.612, 21.504, 18.699 ppm;UV 242.0, 310.0 nm.

Example 933-ethyl-4-methyl-1-((6-methyl-2-p-tolyl-H-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-pyrrol-2(5H)-one(93)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 3-ethyl-4-methyl-1H-pyrrol-2(5H)-one in 84% yield; m/e⁺ 360.4 forC₂₃H₂₆N₃O (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 8.119 (s, 1H), 7.63 (d,J=8.065 Hz, 2H), 7.49 (d, J=8.798 Hz, 1H), 7.25 (d, J=8.065 Hz, 2H),7.04 (d, J=9.165 Hz, 1H), 5.071 (s, 2H, D, CH₂), 3.428 (s, 2H, D, CH₂),2.384 (s, 3H, D, CH₃), 2.294 (s, 3H, D, CH₃), 2.26 (q, 2H, D, CH₂),1.821 (s, 3H, D, CH₃), 1.03 (t, J=7.698 Hz, 3H, D, CH₃) ppm.

Example 944-methoxy-1-((6-methyl-2-p-tolyl-H-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-pyrrol-2(5H)-one(94)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 3-ethyl-4-methyl-1H-pyrrol-2(5H)-one in 84% yield; m/e⁺ 360.4 forC₂₃H₂₆N₃O (M+ and 4-methoxy-1H-pyrrol-2(5H)-one. m/e⁺ 348 for C₂₁H₂₂N₃O₂(M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 8.166 (s, 1H), 7.61 (d, J=8.064 Hz,2H), 7.53 (d, J=9.165 Hz, 1H), 7.27 (d, J=8.798 Hz, 2H), 7.07 (dd,J₁=9.164 Hz, J₂=1.466 Hz, 1H), 5.053 (s, 2H, D, CH₂), 5.053 (s, 1H),3.718 (s, 3H, D, CH₃), 3.551 (s, 2H, D, CH₂), 2.405 (s, 3H, D, CH₃),2.337 (s, 3H, D, CH₃) ppm.

Example 951-((6-methyl-2-p-tolyl-H-imidazo[1,2-a]pyridin-3-yl)methyl)piperidin-2-one(95)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand piperidin-2-one in 39% yield; m/e⁺ 334.4 for C₂₁H₂₄N₃O (M+H)⁺;¹H-NMR (400 MHz, CDCl₃, δ) 8.162 (s, 1H), 7.59 (d, J=8.065 Hz, 2H), 7.51(d, J=9.165 Hz, 1H), 7.26 (d, J=8.065 Hz, 2H), 7.07 (dd, J₁=9.164 Hz,J₂=1.466 Hz, 1H), 5.174 (s, 2H, D, CH₂), 2.83 (m, 2H), 2.40 (s, 3H, D,CH₃), 2.33 (s, 3H, D, CH₃), 1.90 (m, 2H, D, CH₂), 1.70 (m, 2H, D, CH₂),1.60 (m, 2H, D, CH₂) ppm.

Example 961-((6-methyl-2-p-tolyl-H-imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2(1H)-one(96)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand pyridin-2-ol in 76.4% yield; m/e⁺ 330.5 for C₂₁H₂₀N₃O (M+H)⁺; ¹H-NMR(400 MHz, CDCl₃, δ) 8.00 (s, 1H), 7.60 (d, J=8.065 Hz, 2H), 7.53 (d,J=9.165 Hz, 1H), 7.24 (m, 3H), 7.08 (d, J₁=9.146 Hz, J₂=1.1 Hz, 1H),6.82 (dd, J=6.965 Hz, J₂=2.199, 1H), 6.60 (d, J=8.799 Hz, 1H), 5.97 (m,1H), 5.638 (s, 2H, D, CH₂), 2.384 (s, 3H, D, CH₃), 2.290 (s, 3H, D, CH₃)ppm; ¹³C-NMR (100 MHz, CDCl₃, δ) 163.074, 147.029, 144.891, 139.773,138.491, 135.557, 131.060, 129.900, 129.028, 128.535, 123.091, 122.272,121.051, 117.047, 113.976, 107.045, 39.885, 21.542, 18.638 ppm.

Example 973-methyl-1-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2(1H)-one(97)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 3-methylpyridin-2-ol in 63% yield; m/e⁺ 344.3 for C₂₂H₂₂N₃O (M+H)⁺;¹H-NMR (400 MHz, CDCl₃, δ) 7.954 (s, 1H), 7.60 (d, J=8.065 Hz, 2H), 7.54(d, J=9.164, 1H), 7.26 (d, J=8.064, 2H), 7.13 (d, J=6.599 Hz, 1H), 7.09(dd, J=9.164 Hz, J₂=1.1 Hz, 1H), 6.31 (t, J=6.866 Hz, 1H), 5.649 (s, 2H,D, CH₂), 2.388 (s, 3H, D, CH₃), 2.312 (s, 3H, D, CH₃), 2.291 (s, 3H, D,CH₃) ppm.

Example 984,5-dichloro-2-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyridazin-3(2H)-one(98)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 4,5-dichloropyridazin-3(2H)-one. (68.5 mg, 88.2% yield); m/e⁺ 399.3,401.3 (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 7.995 (s, 1H), 7.75 (d, J=8.064Hz, 2H), 7.74 (s, 1H), 7.46 (d, J=9.164 Hz, 1H), 7.20 (d, J=7.699 Hz,2H), 7.10 (d, J=9.165 Hz, 1H), 5.670 (s, 2H, D, CH₂), 2.334 (s, 3H, D,CH₃), 2.287 (s, 3H, D, CH₃) ppm; ¹³C-NMR (100 MHz, CDCl₃, δ) 157.410,156.295, 146.779, 144.459, 138.446, 137.27, 136.77, 130.598, 129.506,129.263, 128.671, 123.25, 122.173, 116.433, 113.491, 45.216, 21.375,18.502 ppm.

Example 993-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-4(3H)-one(99)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand pyrimidin-4(3H)-one (or pyrimidin-4-ol) (41.3 mg, 64% yield); m/e⁺331.4 for C₂₀H₁₉N₄O (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 8.026 (s, 1H),7.80 (d, J=6.598 Hz, 1H), 7.648 (s, 1H), 7.57 (m, 3H), 7.29 (d, J=8.065Hz, 2H), 7.13 (d, J=9.165 Hz, 1H), 6.47 (d, J=6.598 Hz, 1H), 5.638 (s,2H, D, CH₂), 2.416 (s, 3H, D, CH₃), 2.340 (s, 3H, D, CH₃) ppm; ¹³C-NMR(100 MHz, CDCl₃, δ) 161.437, 153.528, 150.381, 147.393, 145.050,138.817, 130.772, 130.044, 129.210, 128.634, 123.356, 122.044, 117.275,115.902, 113.021, 37.906, 21.542, 18.653 ppm; UV 244 nm.

Example 1001-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-one(100)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloridand 2-hydroxypyrimidine. M/e⁺ 331.4 for C₂₀H₁₉N₄O (M+H)⁺; ¹H-NMR (400MHz, CDCl₃, δ) 8.54 (dd, J₁=4.032 Hz, J₂=3.299 Hz, 1H), 7.989 (s, 1H),7.59 (d, J=8.063 Hz, 2H), 7.58 (d, J=9.531 Hz, 1H), 7.29 (d, J=8.065 Hz,1H), 7.16 (m, 2H), 6.15 (dd, J₁=6.595 Hz, J₂=4.032 Hz, 1H), 5.646 (s,2H, D, CH₂), 2.416 (s, 3H, D, CH₃), 2.337 (s, 3H, D, CH₃) ppm. ¹³C-NMR(75 MHz, CDCl₃, δ) 166.318, 156.976, 147.675, 145.818, 145.284, 138.921,130.688, 130.093, 129.519, 128.424, 123.723, 121.934, 117.306, 112.372,105.120, 42.327, 21.574, 18.649 ppm; UV 240, 306 nm.

Example 1015,5-dimethyl-3-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)oxazolidine-2,4-dione(101)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloridand 5,5-dimethyloxazolidine-2,4-dione. m/e⁺ 364.4 for C₂₁H₂₂N₃O₃ (M+H)⁺;¹H-NMR (400 MHz, CDCl₃, δ) 8.08 (s, 1H), 7.74 (d, J=8.0 Hz, 2H), 7.56(d, J=9.1 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.10 (d, J=9.1 Hz, 1H), 5.14(s, 2H, D, CH₂), 2.40 (s, 3H, D, CH₃), 2.35 (s, 3H, D, CH₃), 1.48 (s,6H, D, 2×CH₃) ppm.

Example 1021-methyl-3-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)imidazolidine-2,4-dione(102)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloridand 1-methylimidazolidine-2,4-dione. m/e⁺ 349.4 for C₂₀H₂₁N₄O₂ (M+H)⁺;¹H-NMR (400 MHz, CDCl₃, δ) 8.23 (s, 1H), 7.81 (d, J=7.7 Hz, 2H), 7.54(d, J=9.1 Hz, 1H), 7.28 (d, J=7.7 Hz, 2H), 7.08 (dd, J₁=9.1 Hz, J₂=1.1,1H), 5.12 (s, 2H, D, CH₂), 3.81 (s, 2H, D, CH₂), 2.95 (s, 3H, D, CH₃),2.40 (s, 3H, D, CH₃), 2.36 (s, 3H, D, CH₃) ppm.

Example 1031-(6-Methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-ylmethyl)-1H-pyrimidine-2-thione(103)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand pyrimidine-2(1H)-thione. m/e⁺ 367 for C₂₀H₁₉N₄S [M+H]⁺; ¹H-NMR (300MHz, CDCl₃) δ 8.54 (d, J=4.8 Hz, 2H), 7.94 (d, J=4.8 Hz, 1H), 7.74 (m,2H), 7.56 (d, J=9.0 Hz, 1H), 7.27 (dd, J=4.2, 7.8 Hz, 2H), 7.05 (m, 2H),4.94 (s, 2H), 2.40 (s, 3H), 2.33 (s, 3H) ppm.

Example 1041-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2(1H)-one(104)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride and pyridin-2(1H)-one or pyridin-2-ol in 71% yield; m/e⁺370.2 (100%), 372.2 (60%), 374.2 (20%) for C₁₉H₁₄C₁₂N₃O (M+H)⁺; ¹H-NMR(400 MHz, CDCl₃, δ) 8.54 (d, J=0.733 Hz, 1H), 7.67 (d, J=8.065 Hz, 2H),7.58 (d, J=9.531 Hz, 1H), 7.48 (d, J=8.431 Hz, 2H), 7.25 (m, 2H), 6.78(dd, J₁=6.598 Hz, J₂=1.833 Hz, 1H), 6.54 (d, J=9.164 Hz, 1H), 6.03 (t,6.965 Hz, 1H), 5.64 (s, 2H, D, CH₂) ppm; ¹³C-NMR (100 MHz, CDCl₃, δ)162.915, 146.506, 144.193, 140.008, 135.534, 135.109, 132.053, 130.067,129.566, 127.701, 123.242, 121.817, 121.392, 118.086, 115.986, 107.409,39.597 ppm. UV 226, 308 nm.

Example 1051-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-methylpyrimidin-2(1H)-one(105)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand 4-methylpyrimidin-2(1H)-one or 4-methylpyrimidin-2-ol. m/e⁺ 351 forC19H16ClN4O (M+H)⁺.

Example 1064-amino-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-one(106)

The title compound was prepared according to Method B and theexperimentals described for compound913-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride and 4-methylpyrimidin-2(1H)-one. m/e⁺ 352 for C18H15ClN5O(M+H)⁺.

Example 1071-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-6-methylpyridin-2(1H)-one(107)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride and 6-methylpyridin-2(1H)-one. m/e⁺ 384.3 (100%), 386.3(60%), 387.3 (10%) for C₂₀H₁₆Cl₂N₃O (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ)8.85 (d, J=1.466 Hz, 1H), 7.57 (d, J₁=8.432 Hz, J₂=1.833 Hz, 2H), 7.47(d, J=8.431 Hz, 2H), 7.18 (m, 2H), 6.57 (d, J=9.164 Hz, 1H), 6.89 (d,J=6.965 Hz, 1H), 5.85 (s, 2H, D, CH₂), 1.757 (s, 3H, D, CH₃) ppm; UV242, 310 nm.

Example 1085-chloro-1-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2(1H)-one(108)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride and 5-chloropyridin-2(1H)-one in 88% yield; m/e⁺ 404.2(96%), 406.2 (100%), 408.2 (30%), 407.2 (20%) for C₁₉H₁₃Cl₃N₃O (M+H)⁺;¹H-NMR (400 MHz, CDCl₃, δ) 8.44 (d, J=1.1 Hz, 1H), 7.62 (d, J=8.431 Hz,2H), 7.58 (d, J=9.531 Hz, 1H), 7.48 (m, 2H), 7.21 (m, 2H), 6.74 (d,J=2.932 Hz, 1H), 6.58 (d, J=9.898 Hz, 1H), 5.57 (s, 2H, D, CH₂) ppm;¹³C-NMR (100 MHz, CDCl₃, δ) 161.323, 146.878, 144.330, 141.130, 135.352,133.077, 131.773, 130.082, 129.672, 127.906, 123.007, 122.158, 122.037,118.253, 115.341, 113.779, 39.946 ppm. UV 226, 308 nm.

Example 1091-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-3-methylpyridin-2(1H)-one(109)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride and 3-methylpyridin-2(1H)-one in 85% yield; m/e⁺ 384.3(100%), 386.3 (60%), 347.3 (15%) for C₂₀H₁₆Cl₂N₃O (M+H)⁺; ¹H-NMR (400MHz, CDCl₃, δ) 8.47 (d, J=1.838 Hz, 1H), 7.64 (d, J=8.431 Hz, 2H), 7.55(t, J=9.531 Hz, 1H), 7.44 (d, J=8.431 Hz, 2H), 7.22 (dd, J₁=9.531 Hz,J₂=1.833 Hz, 1H), 7.13 (d, J=6.598 Hz, 1H), 6.65 (d, J=6.965 Hz, 1H),5.93 (t, J=6.599 Hz, 1H), 5.625 (s, 2H, D, CH₂), 2.175 (s, 3H, D, CH₃)ppm; ¹³C-NMR (100 MHz, CDCl₃, δ) 163.332, 146.453, 144.163, 137179,135.041, 132.683, 132.069, 130.514, 130.036, 129.513, 127.602, 123.212,121.756, 118.063, 116.084, 107.030, 39.968, 17.713 ppm. UV 226, 308 nm.

Example 1102-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-6-methylpyridazin-3(2H)-one(110)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride and 6-methylpyridazin-3(2H)-one in 28% yield; m/e⁺ 385.3(100%), 387.3 (60%), 386.3 (20%), 388.3 (14%), 389.2 9 (10%) forC₁₉H₁₅Cl₂N₄O (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 8.78 (d, J₁=1.833 Hz,J₂=0.733 Hz, 1H), 8.09 (dd, J₁=6.965 Hz, J₂=2.199 Hz, 2H), 7.54 (dd,J₁=9.531 Hz, J₂=0.733 Hz, 1H), 7.46 (d, J=8.431 Hz, 2H), 7.20 (dd,J₁=9.531 Hz, J₂=2.2 Hz, 1H), 7.09 (d, J=9.531 Hz, 1H), 6.95 (d, J=9.531Hz, 1H), 5.674 (s, 2H, D, CH₂), 2.277 (s, 3H, D, CH₃) ppm; ¹³C-NMR (100MHz, CDCl₃, δ) 160.087, 146.499, 145.611, 143.807, 134.639, 133.775,132.448, 130.514, 130.431, 128.982, 127.011, 123.712, 121.149, 117.912,116.676, 43.214, 21.087 ppm. UV 226, 308 nm.

Example 1113-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)oxazolidin-2-one(111)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride and oxazolidin-2-one. m/e⁺ 362.3 (100%), 364.3 (65%) forC₁₇H₁₄Cl₂N₃O₂ (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 8.44 (d, J=1.1 Hz, 1H),7.64 (dd, J₁=8.431 Hz, J₂=1.832 Hz, 2H), 7.59 (d, J=9.531 Hz, 1H), 7.446(dd, J₁=6.598 Hz, J₂=1.833 Hz, 2H), 7.26 (dd, J₁=9.531 Hz, J₂=1.833 Hz,1H), 4.933 (s, 2H, D, CH₂), 4.27 (t, J=7.698 Hz, 2H), 3.29 (t, J=8.065Hz, 2H) ppm.

Example 1121-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)pyrrolidin-2-one(112)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride and pyrrolidin-2-one. m/e⁺ 360.3 (100%), 362.3 (65%) forC₁₈H₁₆Cl₂N₃O (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 8.48 (d, J=1.1 Hz, 1H),7.66 (d, J₁=8.431 Hz, 2H), 7.57 (d, J=9.531 Hz, 1H), 7.45 (d J₁=8.431Hz, 2H), 7.21 (dd, J₁=9.531 Hz, J₂=1.833 Hz, 1H), 4.928 (s, 2H, D, CH₂),3.09 (t, J=6.965 Hz, 2H), 2.43 (t, J=8.065 Hz, 2H), 1.92 (m, 2H) ppm.

Example 1131-[6-Chloro-2-(4-chloro-phenyl)-imidazo[1,2-a]pyridin-3-ylmethyl]-azetidin-2-one(113)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride and azetidin-2-one. m/e⁺ 346 for C₁₇H₁₄Cl₂N₃O₄ [M+H]⁺;¹H-NMR (400 MHz, CDCl₃) δ 8.44 (s, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.59 (d,J=9.5 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.25 (m, 1H), 4.79 (s, 2H), 3.18(t, J=4.0 Hz, 2H), 3.00 (t, J=4.0 Hz, 2H) ppm; ¹³C-NMR (100 MHz, CDCl₃,δ) 168.269, 145.293, 143.807, 134.791, 132.129, 129.877, 129.324,127.269, 122.325, 121.771, 118.185, 115.333, 39.400, 37.512, 35.449 ppm.

Example 1141-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)-4-methoxy-1H-pyrrol-2(5H)-one(114)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride and 4-methoxy-1H-pyrrol-2(5H)-one. m/e⁺ 388.3 (100%),390.3 (65%) for C₁₉H₁₆Cl₂N₃O₂ (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 8.58(d, J=1.1 Hz, 1H), 7.66 (d, J=8.431 Hz, 2H), 7.56 (d, J=9.531 Hz, 1H),7.46 (d, J=8.431 Hz, 2H), 7.22 (dd, J₁=9.531 Hz, J₂=1.466 Hz, 1H), 5.082(s, 1H), 5.038 (s, 2H, D, CH₂), 3.742 (s, 3H, D, CH₃), 3.562 (s, 2H, D,CH₂) ppm.

Example 1151-(6-Chloro-2-phenyl-imidazo[1,2-a]pyridin-3-ylmethyl)-azetidin-2-one(115)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from6-chloro-3-(chloromethyl)-2-phenylimidazo[1,2-a]pyridine hydrochlorideand azetidin-2-one. m/e⁺ 312 for C₁₇H₁₅ClN₃O [M+H]⁺; ¹H-NMR (400 MHz,CDCl₃) δ 8.45 (d, J=1.4 Hz, 1H), 7.72 (d, J=1.4, 3.3 Hz, 2H), 7.62 (d,J=9.5 Hz, 1H), 7.49 (m, 2H), 7.25 (dd, J=2.5, 9.5 Hz, 2H), 4.81 (t,J=4.0 Hz, 2H), 3.20 (t, J=4.0 Hz, 2H), 3.00 (t, J=4.0 Hz, 2H) ppm.

Example 1161-(6,8-Dichloro-2-p-tolyl-imidazo[1,2-a]pyridin-3-ylmethyl)-pyrrolidin-2-one(116)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from6,8-dichloro-3-(chloromethyl)-2-p-tolylimidazo[1,2-a]pyridinehydrochloride and pyrrolidin-2-one. m/e⁺ 374 for C₁₉H₁₈Cl₂N₃O [M+H]⁺;¹H-NMR (300 MHz, CDCl₃) δ 8.49 (d, J=1.5 Hz, 1H), 7.63 (d, J=8.1 Hz,2H), 7.33 (m, 3H), 4.93 (s, 2H), 3.11 (t, J=6.9 Hz, 2H), 2.43 (m, 5H),1.92 (m, 2H) ppm.

Example 1172-(6,8-Dichloro-2-p-tolyl-imidazo[1,2-a]pyridin-3-ylmethyl)-6-methyl-2H-pyridazin-3-one(117)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from6,8-dichloro-3-(chloromethyl)-2-p-tolylimidazo[1,2-a]pyridinehydrochloride and 6-methylpyridazin-3(2H)-one. m/e⁺ 399 for C₂₀H₁₇Cl₂N₄O[M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ 8.72 (d, J=1.8 Hz, 1H), 8.01 (d, J=8.1Hz, 2H), 7.30 (m, 3H), 7.10 (d, J=9.3 Hz, 1H), 6.96 (d, J=9.3 Hz, 1H),5.70 (s, 2H), 2.43 (s, 3H), 2.29 (s, 3H) ppm.

Example 1182-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-indazol-3(2H)-one(118)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand 1H-indazol-3(2H)-one. M/e⁺ 375 for C₂₁H₁₆ClN₄O (M+H)⁺; ¹H-NMR (400MHz, CDCl₃) δ 11.11 (bs, 1H), 8.16 (d, J=6.9 Hz, 1H), 8.01 (d, J=7.7 Hz,1H), 7.64 (m, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 1H), 7.30(t, J=7.3 Hz, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.75 (t, J=7.7 Hz, 1H), 6.60(t, J=7.7 Hz, 1H), 6.27 (d, J=8.4 Hz, 1H), 5.34 (s, 2H) ppm.

Example 1192-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(119)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand [1,2,4]triazolo[4,3-a]pyridin-3(2H)-one. M/e⁺ 376 for C₂₀H₁₅ClN₅O(M+H)⁺; ¹H-NMR (400 MHz, CDCl₃) δ 8.68 (d, J=6.9 Hz, 1H), 8.18 (d, J=8.4Hz, 2H), 7.80 (d, J=7.3 Hz, 1H), 7.63 (d, J=9.1 Hz, 1H), 7.50 (d, J=8.4Hz, 2H), 7.25 (m, 1H), 7.09 (dd, J=4.0, 2.9 Hz, 2H), 6.89 (m, 1H), 6.52(m, 1H), 5.54 (s, 2H) ppm.

Example 1201-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-6-methylpyridin-2(1H)-one(120)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from3-(chloromethyl)-2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridinehydrochloride and 6-methylpyridin-2(1H)-one. ¹H-NMR (CDCl₃, 400 MHz, δ)8.75 (dd, J=2.2, 4.6 Hz, 1H), 7.55 (m, 3H), 7.45 (m, 2H), 7.16 (m, 2H),6.55 (d, J=9.1 Hz, 1H), 5.87 (d, J=6.8 Hz, 1H), 5.84 (s, 2H), 1.74 (s,3H) ppm; m/e 368 (M+H)⁺

Example 1211-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-3-methylpyridin-2(1H)-one(121)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from3-(chloromethyl)-2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridinehydrochloride and 3-methylpyridin-2(1H)-one. ¹H-NMR (CDCl₃, 400 MHz, δ)8.43 (dd, J=2.4, 4.1 Hz, 1H), 7.64 (d, J=8.5 Hz, 2H), 7.58 (dd, J=5.0,9.6 Hz, 1H), 7.45 (d, J=8.6 Hz, 2H), 7.17 (m, 1 h), 7.13 (m, 1H), 6.65(dd, J=1.4, 6.9 Hz, 1H), 5.93 (t, J=6.8 Hz, 1H), 5.63 (s, 2H), 2.16 (s,3H) ppm; m/e368 (M+H)⁺

Example 1221-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2(1H)-one(122)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from3-(chloromethyl)-2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridinehydrochloride and pyridin-2-ol. ¹H-NMR (CDCl₃, 400 MHz, δ) 8.45 (dd,J=2.4, 4.0 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.58 (dd, J=5.1, 9.8 Hz,1H), 7.46 (d, J=8.4 Hz, 1H), 7.24 (m, 1H), 7.16 (m, 1H), 6.76 (dd,J=1.9, 6.9 Hz, 1H), 6.59 (d, J=9.1 Hz, 1H), 6.00 (m, 1H), 5.62 (s, 2H)ppm; me/354 (M+H)⁺

Example 1231-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidine-2,4(1H,3H)-dione(123)

The title compound was prepared according to Method B and theexperimentals described for compound 91 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand pyrimidine-2,4(1H,3H)-dione. M/e⁺ 353 for C₁₈H₁₄ClN₄O₂ (M+H)⁺;¹H-NMR (400 MHz, CDCl₃) δ 8.33 (d, J=5.8 Hz, 1H), 8.10 (s, 1H), 7.81 (d,J=8.4 Hz, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.39 (td,J=6.9, 1.1 Hz, 1H), 7.00 (td, J=6.9, 1.1 Hz, 1H), 6.66 (d, J=8.0 Hz,1H), 5.58 (d, J=8.0 Hz, 1H), 5.45 (s, 2H) ppm.

Example 1244-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(124)

The title compound was prepared according to Method B and theexperimentals described for compound 92 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand 2H-benzo[b][1,4]oxazin-3(4H)-one. M/e⁺ 390 for C₂₂H₁₇ClN₃O₂ (M+H)⁺;¹H-NMR (400 MHz, CDCl₃) δ 8.32 (d, J=6.9 Hz, 1H), 7.61 (d, J=8.4 Hz,2H), 7.53 (m, 3H), 7.19 (ddd, J=9.1, 6.9, 1.1 Hz, 1H), 6.82 (m, 3H),6.48 (m, 1H), 6.26 (d, J=7.7 Hz, 1H), 5.68 (s, 2H), 4.60 (s, 2H) ppm.

Example 1251-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-3-methylpyrimidine-2,4(1H,3H)-dione(125)

The title compound was prepared according to Method B and theexperimentals described for compound 92 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand 3-methylpyrimidine-2,4(1H,3H)-dione. M/e⁺ 367 for C₁₉H₁₆ClN₄O₂(M+H)⁺; ¹H-NMR (400 MHz, CDCl₃) δ 8.22 (d, J=5.8 Hz, 1H), 7.66 (d, J=8.4Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.30 (m, 1H), 6.91 (t, J=6.6 Hz, 1H),6.63 (d, J=8.0 Hz, 1H), 5.56 (d, J=8.0 Hz, 1H), 5.45 (s, 2H), 5.26 (d,J=0.7 Hz, 1H), 3.34 (s, 3H) ppm.

Example 126 Ethyl1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(126)

The title compound was prepared according to Method B and theexperimentals described for compound 92 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate. M/e⁺ 425for C₂₁H₁₈ClN₄O₄ (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃) δ 9.72 (s, 1H), 8.32(d, J=6.9 Hz, 1H), 7.67 (m, 4H), 7.48 (d, J=8.4 Hz, 2H), 7.31 (t, J=7.3Hz, 1H), 6.93 (t, J=6.96 Hz, 1H), 5.49 (s, 2H), 4.10 (q, J=6.9 Hz, 2H),1.16 (t, J=6.9 Hz, 3H) ppm.

Example 1271-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-5-fluoropyrimidine-2,4(1H,3H)-dione(127)

The title compound was prepared according to Method B and theexperimentals described for compound 92 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand 5-fluoropyrimidine-2,4(1H,3H)-dione. M/e⁺ 371 for C₁₈H₁₃ClFN₄O₂(M+H)⁺; ¹H-NMR (400 MHz, CDCl₃) δ 8.22 (d, J=6.9 Hz, 1H), 7.71 (d, J=8.8Hz, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.36 (m, 1H),6.96 (m, 1H), 6.69 (d, J=5.5 Hz, 1H), 5.45 (s, 2H) ppm.

Example 1286-chloro-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidine-2,4(1H,3H)-dione(128)

The title compound was prepared according to Method B and theexperimentals described for compound 92 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand 6-chloropyrimidine-2,4(1H,3H)-dione. M/e⁺ 387 for C₁₈H₁₃Cl₂N₄O₂(M+H)⁺; ¹H-NMR (400 MHz, CDCl₃) δ 9.35 (bs, 1H), 8.44 (d, J=6.23 Hz,1H), 7.66 (d, J=9.1 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz,2H), 7.29 (m, 2H), 6.90 (t, J=6.9 Hz, 1H), 5.74 (d, J=8.0 Hz, 2H) ppm.

Example 1293-Methylsulfanyl-4-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-ylmethyl)-4H-[1,2,4]thiadiazole-5-thione(129)

The title compound was prepared according to Method A and theexperimentals described for compound 92 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 3-(methylthio)-1,2,4-thiadiazole-5(4H)-thione. m/e⁺ 399 forC₁₉H₁₉N₄S₃ [M+H]⁺; ¹H-NMR (400 MHz, CDCl₃) δ 7.96 (s, 1H), 7.67 (d,J=7.7 Hz, 2H), 7.57 (d, J=9.1 Hz, 1H), 7.27 (d, J=8.0 Hz, 2H), 7.11 (d,J=9.1 Hz, 1H), 5.04 (s, 2H), 2.67 (s, 3H), 2.39 (s, 3H), 2.36 (s, 3H)ppm; ¹³C-NMR (100 MHz, CDCl₃, δ) 186.346, 171.423, 145.801, 144.701,138.203, 130.870, 129.680, 128.573, 128.300, 122.825, 121.733, 117.047,111.982, 29.739, 21.444, 18.577, 14.968, ppm.

Example 1304,5-Dimethyl-3-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-ylmethyl)-3H-thiazole-2-thione(130)

The title compound was prepared according to Method A and theexperimentals described for compound 92 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 4,5-dimethylthiazole-2(3H)-thione. m/e⁺ 380 for C₂₁H₂₂N₃S₂ [M+H];¹H-NMR (400 MHz, CDCl₃) δ 7.96 (s, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.55 (d,J=8.8 Hz, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.08 (dd, J=1.4, 9.1 Hz, 1H),4.83 (s, 2H), 2.39 (s, 3H), 2.35 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H)ppm; ¹³C-NMR (100 MHz, CDCl₃, δ) 156.250, 149.085, 145.149, 144.391,137.642, 131.159, 129.347, 128.748, 128.217, 127.929, 122.090, 121.794,116.828, 113.612, 30.301, 21.308, 18.449, 14.688, 11.374 ppm.

Example 1313-((6-Methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)thiazole-2(3H)-thione(131)

The title compound was prepared according to Method A and theexperimentals described for compound 92 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand thiazole-2(3H)-thione. m/e⁺ 352 for C₁₉H₁₈N₃S₂ [M+H]⁺; ¹H-NMR (400MHz, CDCl₃) δ 7.96 (s, 1H), 7.73 (d, J=3.3 Hz, 1H), 7.68 (d, J=8.0 Hz,2H), 7.56 (d, J=9.1 Hz, 1H), 7.27 (m, 3H), 7.08 (dd, J=1.1, 9.1 Hz, 1H),4.97 (s, 2H), 2.39 (s, 3H), 2.34 (s, 3H) ppm; ¹³C-NMR (100 MHz, CDCl₃,δ) 162.749, 145.233, 144.444, 142.927, 137.779, 131.022, 129.430,128.164, 128.096, 122.310, 121.643, 120.225, 116.850, 112.983, 29.808,21.300, 18.426 ppm.

Example 1321-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-(ethylamino)pyrimidin-2(1H)-one(132)

Step 1: To a solution of142-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidine-2,4(1H,3H)-dione(500 mg, 1.42 mmol) in CH₂Cl₂ (10 mL) at 0° C. was added POCl₃ (0.3 ml).The mixture was refluxed for 4 hours and cooled to room temperature andpoured onto ice-water (10 ml). The mixture was neutralized with aqueousammmnia hydroxide to pH˜7-8 and extracted with CH₂Cl₂ (3×20 mL). Thecombined organic solution was washed with water, sat. NaHCO₃ and brine,dried and evaporated. The crude product was purified by silica gelchromatphraphy. m/e⁺ 372 for C18H13N4O [M+H)⁺.

Step 2: A mixture of4-chloro-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-one(50 mg, 0.13 mmol) and ethylamine (30 μl) in ethanol (2 ml) in a sealedtube was heated at 70 oC for 4 hours. Excess reaget was evaporated underreduced pressure. Crude product was dissolved in CH₂Cl₂ (10 mL) waswashed with water, sat. NaHCO₃ and brine, dried and evaporated. Thecrude product was purified by silica gel chromatphraphy. M/e⁺ 380 forC₂₀H₁₉ClN₅O (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃) δ 8.42 (d, J=6.6 Hz, 1H),7.68 (d, J=8.4 Hz, 2H), 7.64 (d, J=9.1 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H),7.29 (d, J=7.7 Hz, 1H), 6.87 (t, J=6.9 Hz, 1H), 6.65 (d, J=7.3 Hz, 1H),5.37 (d, J=7.3 Hz, 2H), 4.97 (s, 1H), 3.51 (m, 2H), 3.18 (s, 1H), 1.18(t, J=7.3 Hz, 3H) ppm.

Example 1331-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-(methylamino)pyrimidin-2(1H)-one(133)

The title compound was prepared according to the experimental forcompound 132 from4-chloro-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-oneand methylamine. M/e⁺ 366 for C₁₉H₁₇ClN₅O (M+H)⁺; ¹H-NMR (400 MHz,CDCl₃) δ 8.42 (d, J=6.6 Hz, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.62 (m, 1H),7.46 (d, 8.4 Hz, 2H), 7.28 (d, J=7.7 Hz, 1H), 6.86 (t, J=6.9 Hz, 1H),6.64 (d, J=7.3 Hz, 1H), 5.51 (s, 2H), 5.41 (d, J=7.3 Hz, 1H), 5.24 (bs,1H), 2.98 (s, 3H) ppm.

Example 1341-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-(2-(dimethylamino)ethylamino)pyrimidin-2(1H)-one(134)

The title compound was prepared according to the experimental forcompound 132 from4-chloro-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-oneand N¹,N¹-dimethylethane-1,2-diamine. M/e⁺ 423 for C₂₂H₂₄ClN₆O (M+H)⁺;¹H-NMR (400 MHz, CDCl₃) δ 8.42 (d, J=6.9 Hz, 1H), 7.68 (dd, J=8.4, 2.2Hz, 2H), 7.64 (dd, J=9.1, 1.1 Hz, 1H), 7.47 (dd, J=8.4, 2.2 Hz, 2H),7.28 (d, J=7.7 Hz, 1H), 6.86 (t, J=6.6 Hz, 1H), 6.65 (dd, J=7.3, 2.2 Hz,1H), 6.49 (bs, 1H), 5.54 (d, J=1.8 Hz, 2H), 5.46 (dd, J=7.3, 1.8 Hz,1H), 3.59 (m, 2H), 2.61 (m, 2H), 2.16 (s, 6H) ppm.

Example 1351-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-(dimethylamino)pyrimidin-2(1H)-one(135)

The title compound was prepared according to the experimental forcompound 132 from4-chloro-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-oneand dimethylamine. M/e⁺ 380 for C₂₀H₁₉ClN₅O (M+H)⁺; ¹H-NMR (400 MHz,CDCl₃) δ 8.44 (d, J=6.9 Hz, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.8Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.28 (d, J=6.9 Hz, 1H), 6.86 (t, J=6.6Hz, 1H), 6.75 (d, J=7.7 Hz, 1H), 5.63 (d, J=7.7 Hz, 1H), 5.56 (s, 2H),3.18 (s, 3H), 2.96 (s, 3H) ppm.

Example 1361-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-(pyrrolidin-1-yl)pyrimidin-2(1H)-one(136)

The title compound was prepared according to the experimental forcompound 132 from4-chloro-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-oneand pyrrolidine. M/e⁺ 406 for C₂₂H₂₁ClN₅O (M+H)⁺; ¹H-NMR (400 MHz,CDCl₃) δ 8.44 (d, J=6.6 Hz, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.8Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.28 (m, 1H), 6.86 (td, J=6.9, 1.1 Hz,1H), 6.73 (d, J=7.3 Hz, 1H), 5.57 (s, 2H), 5.49 (d, J=7.7 Hz, 1H), 3.65(t, J=6.6 Hz, 2H), 3.28 (t, J=6.6 Hz, 2H), 1.90 (m, 4H) ppm.

Example 1371-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-ethoxypyrimidin-2(1H)-one(137)

The title compound was prepared according to the experimental forcompound 132 from4-chloro-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-oneand NaOEt in EtOH. M/e⁺ 381 for C₂₀H₁₈ClN₄O₂ (M+H)⁺; ¹H-NMR (400 MHz,CDCl₃) δ 8.36 (d, J=7.0 Hz, 1H), 8.17 (s, 1H), 7.66 (d, J=8.4 Hz, 2H),7.48 (d, J=8.4 Hz, 2H), 7.30 (m, 1H), 6.92 (m, 1H), 6.89 (d, J=6.9 Hz,1H), 5.71 (d, J=6.9 Hz, 1H), 5.60 (s, 2H), 4.40 (q, J=6.9 Hz, 2H), 1.32(t, J=6.9 Hz, 3H) ppm.

Example 1381-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-(1H-1,2,4-triazol-1-yl)pyrimidin-2(1H)-one(138)

The title compound was prepared according to the experimental forcompound 132 from4-chloro-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-oneand 1H-1,2,4-triazole in DMF. M/e⁺ 404 for C₂₀H₁₅ClN₇O (M+H)⁺; ¹H-NMR(400 MHz, CDCl₃) δ 9.24 (d, J=1.8 Hz, 1H), 8.33 (d, J=6.6 Hz, 1H), 8.18(d, J=1.8 Hz, 2H), 8.06 (d, J=1.8 Hz, 1H), 7.67 (m, 1H), 7.66 (dd,J=8.4, 1.8 Hz, 1H), 7.49 (dd, J=8.4, 1.8 Hz, 2H), 7.34 (m, 1H), 6.95 (t,J=6.6 Hz, 1H), 6.90 (dd, J=7.3, 1.8 Hz, 1H), 5.27 (s, 2H) ppm.

General Procedures for Formula IV, Method A

A mixture of 3-(chloromethyl)-imidazo[1,2-a]pyridine HCl salt (0.20mmol), hetereoaromatic amines or ArQH (Q=O or S) (0.42 mmol, 2.0 eq) inAcCN (1-2 ml) and K₂CO₃ (4 eq) was heated at 65° C. overnight. Themixture was treated with sat. NaHCO₃ (5 ml), extracted with CH₂Cl₂ (10ml). The organic solution was dried with Na₂SO₄, evaporated undervacuum. The crude product was purified by silica gel columnchromatography (12 g silica gel RediSep column, eluted first with 10%ethyl acetate in hexane, then 20% acetone in hexane to afford a whitesolid. The product shows up as violet spot on TLC plate under UV light.For larger scale reaction (>1 g), the corresponding HCl salt can beobtained by the following simplified work up procedures: After thereaction was complete as judged by LC-mass analysis, the mixture wascooled down to room temperature and the white solid was collected byfiltration. Then the solid was suspended in 30-40 ml of EtOH (for 1 gramos starting material) and stirred at 50° C. for a few hours. After beingcooled by ice water, the white solid was collected by filtration andrinsed with cool ethanol. The product was dried under reduced pressure.

Example 139N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine(139)

A mixture of 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridinehydrochloride (0.20 mmol), pyrimidin-2-amine (0.42 mmol, 2.0 eq) in AcCN(2 ml) and K₂CO₃ (4 eq) was heated at 65° C. overnight. The mixture wastreated with sat. NaHCO₃ (5 ml), extracted with CH₂Cl₂ (10 ml). Theorganic solution was dried with Na₂SO₄, evaporated under vacuum. Thecrude product was purified by silica gel column chromatography (12 gsilica gel RediSep column, eluted first with 10% ethyl acetate inhexane, then 20% acetone in hexane to afford a white solid. The productshows up as violet spot on TLC plate under UV light. m/e⁺ 330.5 forC₂₀H₂₀N₅ (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 8.05 (broad, 1H), 7.902 (s,1H), 7.66 (d, J=8.065 Hz, 2H), 7.53 (d, J=9.164 Hz, 1H), 7.23 (d,J=7.698 Hz, 2H), 7.03 (dd, J₁=9.164 Hz, J₂=1.466 Hz, 1H), 6.47 (t,J=5.132 Hz, 1H), 6.32 (t, J=4.399 Hz, 1H, D, NH), 5.00 (d, J=4.765 Hz,2H, D, CH₂). 2.383 (s, 3H, D, CH₃), 2.263 (s, 3H, D, CH₃) ppm; ¹³C-NMR(100 MHz, CDCl₃, δ) 162.347 (C═NH, D, Pyrimidine), 158.100 (2 C═N,Pyrimidine), 144.499 (Tolyl C═N, imidazopyridine), 144.375 (N—C—N,imidazopyridine) 137.869, 131.500, 129.612, 128.452, 128.103, 122.188,122.097, 116.956, 116.304, 111.307 (CH, D, pyrimidine), 35.707 (CH₂),21.520 (CH₃), 18.600 (CH₃) ppm.

Example 140

N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2-amine(140)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand pyridin-2-amine. m/e⁺ 329.4 for C₂₁H₂₁N₄ (M+H)⁺; ¹H-NMR (400 MHz,CDCl₃, δ); 8.19 (dd, J=4.032 Hz, J₂=0.733 Hz, 1H), 7.926 (s, 1H), 7.66(d, J=8.065 Hz, 2H), 7.53 (d, J=9.164 Hz, 1H), 7.23 (d, J=8.065 Hz, 2H),7.06 (dd, J₁=9.164 Hz, J₂=1.466 Hz, 1H), 6.67 (d, J=6.232 Hz, J₂=5.132Hz, 1H), 6.47 (d, J=8.431 Hz, 1H), 4.95 (d, J=4.766 Hz, 2H, D, CH₂),4.56 (t, 1H, D, J=4.398 Hz, 1H, D, NH), 2.385 (s, 3H, D, CH₃), 2.295 (s,3H, D, CH₃) ppm; ¹³C-NMR (100 MHz, CDCl₃, δ) 158.631, 148.174, 144.466,144.262, 137.627, 137.551, 131.379, 129.506, 128.209, 127.997, 122.082,116.744, 116.463, 113.582, 108.645, 35.980, 21.497, 18.532 ppm.

Example 1415-bromo-N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine(141)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 5-bromopyrimidin-2-amine. m/e⁺ 408 (100%), 410 (98%) for C₂₀H₁₉BrN₅(M+H)⁺.

Example 1424,6-dichloro-N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine(142)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 4,6-dichloropyrimidin-2-amine. m/e⁺ 398.3, 3 (100%), 399.3 (65%) forC₂₀H₁₈Cl₂N₅ (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 8.072 (s, 1H), 7.63 (d,J=8.064 Hz, 2H), 7.55 (d, J=9.531 Hz, 1H), 7.27 (d, J=8.432, 2H), 7.08(d, J=9.165 Hz, 1H), 6.707 (s, 1H), 5.544 (t, 1H, D, NH), 5.02 (d,J=5.499 Hz, 2H, D, CH₂), 2.406, (s, 3H, D, CH₃), 2.350 (s, 3H, D, CH₃)ppm.

Example 1434-methyl-N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine(143)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 4-methylpyrimidin-2-amine (52.9 mg, 79% yield). M/e⁺ 344.4 forC₂₁H₂₂N₅ (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 7.938 (s, 1H), 7.64 (d,J=8.065 Hz, 2H), 7.49 (d, J=9.165 Hz, 1H), 7.20 (d, J=7.698, 2H), 7.00(d, J=9.165 Hz, 1H), 6.35 (d, J=4.766 Hz, 1H), 6.10 (broad, 1H, D, NH),4.97 (d, J=4.765 Hz, 2H, D, CH₂), 2.358 (s, 3H, D, CH₃), 2.221 (s, 3H,D, CH₃) ppm; ¹³C-NMR (100 MHz, CDCl₃, δ) 168.344, 162.256, 157.56,144.770, 144.262, 137.771, 131.52, 129.544, 128.444, 127.989, 122.219,122.037, 116.827, 116.585, 111.004, 35.684, 24.204, 21.489, 18.577 ppm.UV 244.0, 306.0 nm.

Example 144

N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrazin-2-amine(144)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand pyrazin-2-amine. m/e⁺ 330.4 for C₂₀H₂₀N₅ (M+H)⁺; ¹H-NMR (400 MHz,CDCl₃, δ) 8.07 (d, J=3.66 Hz, 2H), 7.86 (d, J=2.566 Hz, 1H), 7.73 (s,1H), 7.51 (d, J=8.064 Hz, 2H), 7.45 (d, J=9.164 Hz, 1H), 7.12 (d,J=8.065, 2H), 7.00 (d, J=9.165 Hz, 1H), 5.58 (t, 1H, D, NH), 4.88 (d,J=4.765 Hz, 2H, D, CH₂), 2.34 (s, 3H, D, CH₃), 2.253 (s, 3H, D, CH₃)ppm; ¹³C-NMR (100 MHz, CDCl₃, δ) 154.900, 144.436, 144.239, 142.184,141.903, 137.665, 133.873, 133.024, 130.954, 129.483, 128.148, 127.913,122.287, 121.809, 116.638, 115.819, 35.153, 21.451, 18.539 ppm.

Example 145(6-Methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-ylmethyl)-[1,2,4]triazin-3-yl-amine(145)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 1,2,4-triazin-3-amine. m/e⁺ 331 for C₁₉H₁₉N₆ [M+H]⁺; ¹H-NMR (400MHz, CDCl₃) δ 8.60 (d, J=2.2 Hz, 1H), 8.04 (s, 1H), 8.00 (d, J=2.2 Hz,1H), 7.86 (s, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.53 (d, J=9.1 Hz, 1H), 7.22(d, J=8.0 Hz, 2H), 7.05 (dd, J=1.4, 9.1 Hz, 1H), 5.11 (s, 2H), 2.37 (s,3H), 2.27 (s, 3H) ppm.

Example 146(6-Methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-ylmethyl)-[1,3,5]triazin-2-yl-amine(146)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 1,3,5-triazin-2-amine. M/e⁺ 331 for C₁₉H₁₉N₆ (M+H)⁺; ¹H-NMR (400MHz, CDCl₃) δ 8.71 (s, 1H), 8.51 (s, 1H), 8.24 (s, 1H), 7.94 (s, 1H),7.65 (d, J=9.1 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H),7.14 (dd, J=9.1, 1.4 Hz, 1H), 5.06 (d, J=5.1 Hz, 2H), 2.39 (s, 3H), 2.32(s, 3H) ppm.

Example 1474-chloro-6-methyl-N-((6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine(147)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 1,3,5-triazin-2-amine. m/e⁺ m/e+378.1 for C₂₁H₂₀ClN₅ (M+H)⁺; ¹H-NMR(400 MHz, CDCl₃, δ) 8.095 (s, 1H), 7.65 (d, J=8.064 Hz, 2H), 7.55 (d,J=9.164 Hz, 1H), 7.16 (d, J=7.698 Hz, 2H), 7.07 (d, J=9.165 Hz, 1H),6.533 (s, 1H), 5.396 (broad s, 1H, D, NH), 5.02 (d, J=5.132 Hz, 2H),CH2), 2.396 (s, 3H, D, CH3), 2.322 (s, s, 6H, D, 2CH3) ppm.

Example 1484,6-dimethyl-N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine(148)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 4,6-dimethylpyrimidin-2-amine. (49.3 mg, 70% yield) m/e⁺ 358.3 forC₂₂H₂₄N₅ (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 8.11 (s, 1H), 7.68 (d,J=8.065 Hz, 2H), 7.23 (d, J=8.065 Hz, 1H), 7.00 (d, J=9.165 Hz, 2H),6.35 (s, 1H), 5.35 (broad s, 1H, D, NH), 5.03 (d, J=5.132 Hz, 2H, D,CH₂), 2.383 (s, 3H, D, CH₃), 2.275 (s, 6H, D, 2CH₃) ppm.

Example 149N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)isoxazole-3-amine(149)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand isoxazol-3-amine. m/e⁺ 319.4 for C₁₉H₁₉N₄O (M+H)⁺; ¹H-NMR (400 MHz,CDCl₃, δ) 8.11 (d, J=1.833 Hz, 1H), 7.828 (s, 1H), 7.56 (d, J=8.065 Hz,2H), 7.47 9 (d, J=9.164 Hz, 1H), 7.17 (d, J=7.698 Hz, 2H), 7.03 (dd,J₁=9.164 Hz, J₂=1.466 Hz, 1H), 5.92 (d, J=1.833 Hz, 1H), 4.78 (d,J=5.132 Hz, 2H, D, CH₂), 4.38 (t, 1H, D, NH), 2.366 (s, 3H, D, CH₃),2.301 (s, 3H, D, CH₃) ppm; ¹³C-NMR (100 MHz, CDCl₃, δ) 163.820, 158.512,144.683, 144.436, 137.919, 131.188, 129.613, 128.317, 128.204, 122.414,121.934, 116.899, 115.971, 96.620, 38.000, 21.520, 18.595 ppm; UV 244.0,312.0 nm.

Example 150N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)thiazole-2-amine(150)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand thiazol-2-amine. m/e⁺ 335.4 (100%), 336.3 (20%) for C₁₉H₁₉N₄S(M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 6) 7.802 (s, 1H, D, H), 7.56 (d,J=8.064 Hz, 2H, D, 2×H), 7.49 (d, J=9.164 Hz, 1H), 7.17 (d, J=8.065 Hz,2H), 7.04 (m, 2H), 6.238 (broad, 1H, D, NH), 4.848 (s, 2H, D, CH₂),2.363 (s, 3H, D, CH₃), 2.269 (s, 3H, D, CH₃) ppm; ¹³C-NMR (100 MHz,CDCl₃, δ) 169.376, 144.974, 144.451, 139.181, 137.900, 131.060, 129.597,128.361, 128.239, 122.476, 121.893, 116.911, 115.121, 107.622, 39.415,21.504, 18.562 ppm; UV 246.0, 312.0 nm.

Example 1513-methyl-N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)isothiazol-5-amine(151)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 3-methylisothiazol-5-amine. 31.2 mg, 45.5% yield); m/e⁺ 349.3 forC₂₀H₂₁N₄S (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 7.541 (s, 1H), 7.38 (d,J=9.165 Hz, 1H), 7.35 (d, J=8.065 Hz, 2H), 7.04 (d, J=8.064 Hz, 2H),6.97 (d, J=9.164 Hz, 1H), 6.127 (s, 1H), 6.03 (t, 1H, D, NH), 4.41 (d,J=4.4 Hz, 2H, D, CH₂), 2.335 (s, 3H, D, CH₃), 2.320 (s, 3H, D, CH₃),2.231 (s, 3H, D, CH₃) ppm; ¹³C-NMR (100 MHz, CDCl₃, δ) 173.425, 167.154,144.512, 144.284, 137.809, 130.537, 129.536, 128.452, 127.799, 122.589,121.483, 116.706, 114.659, 102.382, 41.235, 21.482, 19.715, 18.547 ppm;UV 242 nm.

Example 152(6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)-N-(4H-1,2,4-triazol-4-yl)methanamine(152)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 4H-1,2,4-triazol-4-amine (36.5 mg, 58.9% yield); m/e⁺ 319.4 forC₁₈H₁₉N₆ (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 7.541 (s, 1H), 7.96 (m, 2H),7.910 (s, 1H), 7.37 (m 2H), 7.16 (m, 2H), 7.07 (m, 3H), 4.47 (s, 2H),3.98 (broad, 1H), 2.276 (s, 3H, D, CH₃), 2.247 (s, 3H, D, CH₃) ppm;¹³C-NMR (100 MHz, CDCl₃, δ) 146.180, 144.391, 142.897, 138.385, 130.271,129.430, 129.248, 128.421, 123.083, 121.877, 116.281, 113.658, 46.831,21.186, 18.282 ppm; UV 242, 308 nm.

Example 153N-((6-methyl-2-p-tolyl-H-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-imidazol-2-amine(153)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 1H-imidazol-2-amine. m/e⁺ 318.4 for C₁₉H₂₀N₅(M+H)⁺; ¹H-NMR (400 MHz,CD₃OD, δ) 8.141 (s, 1H), 7.60 (d, J=8.065 Hz, 2H), 7.48 (d, J=9.164 Hz,1H), 7.27 (d, J=8.432 Hz, 2H), 7.24 (d, J₁=9.164 Hz, J₂=1.467 Hz, 1H),6.716 (s, 2H), 4.905 (s, 2H, D, NH₂), 4.787 (s, 2H, D, CH₂), 2.377 (s,3H, D, CH₃), 2.342 (s, 3H, D, CH₃) ppm; ¹³C-NMR (100 MHz, CD₃OD, δ),149.850, 144.140, 144.034, 138.135, 130.787, 129.195, 129.028, 128.307,123.037, 122.446, 116.736, 116.403, 115.364, 37.163, 20.109, 17.016 ppm.

Example 1541-methyl-N-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methyl)-1H-benzo[d]imidazol-2-amine(154)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 1-methyl-1H-benzo[d]imidazol-2-amine. m/e⁺ 382.4 for C₂₄H₂₄N₅(M+H)⁺; ¹H-NMR (400 MHz, CDCl₃, δ) 8.107 (s, 1H), 8.061 (s, 1H), 7.66(d, J=8.065 Hz, 2H), 7.57 (d, J=7.698 Hz, 1H), 7.53 (d, J=9.164 Hz, 1H),7.24 (d, J=8.065 Hz, 2H), 7.15 (m, 2H), 7.13 (dd, J₁=4.032 Hz, J₂=0.733Hz, 2H), 7.07 (dd, J₁=9.165 Hz, J₂=1.467 Hz, 1H), 5.21 (d, J=4.66 Hz,2H), 3.504 (s, 3H), 2.394 (s, 3H, D, CH₃), 2.284 (s, 3H, D, CH₃) ppm; UV218, 244, 266 nm.

Example 1552-Methyl-3-[(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-ylmethyl)-amino]-3H-quinazolin-4-one(155)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 3-amino-2-methylquinazolin-4(3H)-one. m/e⁺ 410 for C₂₅H₂₄N₅O [M+H]⁺;¹H-NMR (400 MHz, CDCl₃) δ 8.31 (s, 1H), 8.22 (t, J=1.1 Hz, 1H), 7.71 (m,1H), 7.68 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 1H), 7.53 (d, J=9.1 Hz,1H), 7.44 (t, J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 2H), 7.06 (dd, J=1.1,9.1 Hz, 1H), 5.86 (t, J=4.8 Hz, 2H), 4.53 (bs, 1H), 2.42 (s, 3H), 2.33(s, 3H), 2.29 (s, 3H) ppm; ¹³C-NMR (100 MHz, CDCl₃, δ) 161.838, 155.787,147.287, 146.870, 144.648, 137.968, 134.753, 131.113, 129.377, 128.399,128.361, 127.246, 126.736, 126.457, 122.711, 121.779, 120.763, 117.161,114.044, 43.949, 21.906, 21.459, 18.646 ppm.

Example 156N-((6-chloro-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-aminehydrochloride (156)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride and pyrimidin-2-amine. m/e⁺ 300.3 (100%), 372.3 (65%) forC₁₈H₁₄Cl₂N₅ (M+H)⁺; ¹H-NMR (400 MHz, CD₃OD, δ) 9.324 (m, 1H), 8.35 (d,J=5.132 Hz, 2H), 8.06 (dd, J₁=9.531 Hz, J₂=1.833 Hz, 1H), 7.96 (d,J=9.531 Hz, 1H), 7.86 (dd, J₁=6.599 Hz, J₂=1.833 Hz, 2H), 7.67 (dd,J₁=6.598 Hz, J₂=1.833 Hz, 2H), 6.79 (t, 1H, D, J=5.132 Hz, 1H), 5.10 (s,2H, D, CH₂) ppm. ¹³C-NMR (100 MHz, DMSO-d₆-CD₃OD) 159.707, 157.599,138.203, 135.337, 134.305, 133.282, 130.628, 129.066, 125.858, 125.638,123.856, 120.490, 33.774 ppm; UV 246, 312 nm. The salt dissolved slowlyunder heating in DMSO, MeOH. It is not very soluble in CDCl₃, CH₂Cl₂.

Example 157[2-(4-Chloro-phenyl)-imidazo[1,2-a]pyridin-3-ylmethyl]-(4-methyl-pyrimidin-2-yl)-amine(157)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand 4-methylpyrimidin-2-amine. m/e⁺ 350 for C₁₉H₁₇ClN₅ [M+H]⁺; ¹H-NMR(400 MHz, CDCl₃) δ 8.18 (d, J=6.9 Hz, 1H), 7.95 (s, 1H), 7.73 (d, J=8.4Hz, 2H), 7.62 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.20 (m, 1H),6.76 (dt, J=1.1, 6.9 Hz, 1H), 6.42 (d, J=5.1 Hz, 1H), 5.95 (s, 1H), 5.03(d, J=5.1 Hz, 2H) 2.28 (s, 3H) ppm.

Example 158(6-Chloro-2-phenyl-imidazo[1,2-a]pyridin-3-ylmethyl)-(4-methyl-pyrimidin-2-yl)-amine(158)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from6-chloro-3-(chloromethyl)-2-phenylimidazo[1,2-a]pyridine hydrochloride4-methylpyrimidin-2-amine. m/e⁺ 350 for C₁₉H₁₇ClN₅ [M+H]⁺; ¹H-NMR (400MHz, CDCl₃) δ 8.61 (s, 1H), 8.13 (d, J=4.0 Hz, 1H), 7.77 (d, J=6.9 Hz,2H), 7.57 (d, J=9.5 Hz, 1H), 7.47 (m, 2H), 7.39 (s, 1H), 7.17 (dd,J=2.2, 9.5 Hz, 1H), 6.50 (d, J=5.1 Hz, 1H), 5.48 (s, 1H), 5.06 (d, J=5.8Hz, 2H), 2.37 (s, 3H) ppm.

Example 1594-chloro-N-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-6-methylpyrimidin-2-amine(159)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand 4-chloro-6-methylpyrimidin-2-amine. M/e+, 384.1, 386 forC₁₉H₁₅Cl₂N₅. ¹H-NMR (400 MHz, CDCl₃, δ) 8.25 (m, 1H), 7.74 (d, J=6.598Hz, 2H), 7.63 (m, 1H), 7.42 (d, J=6.599 Hz, 2H), 7.24 (m, 1H), 6.84 (m,1H), 6.55 (s, 1H), 5.41 (s, NH), 5.05 (d, J=5.13 Hz, 2H, D, CH2), 2.318(s, 3H, D, CH3) ppm.

Example 1604-chloro-N-((2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)methyl)-6-methylpyrimidin-2-amine(160)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridinehydrochloride and 4-chloro-6-methylpyrimidin-2-amine. H-NMR (400 MHz,CDCl₃) 8.021 (s, 1H), 7.73 (m, 2H), 7.51 (d, J=9.164 Hz, 1H), 7.10 (m,2H), 6.50 (s, 1H), 5.28 (broad, 1H, D, NH), 4.98 (d, J=5.032 Ha, 2H, D,CH2), 2.29 (s, 3H, D, CH3), 2.26 (s, 3H) ppm; m/e+382.0, 384.1 forC20H17ClFN5 (M+H)+

Example 1614-(6-chloro-3-((4-chloro-6-methylpyrimidin-2-ylamino)methyl)imidazo[1,2-a]pyridin-2-yl)benzonitrile(161)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from4-(6-chloro-3-(chloromethyl)imidazo[1,2-a]pyridin-2-yl)benzonitrilehydrochloride and 4-chloro-6-methylpyrimidin-2-amine. m/e+409.0, 411.0for C20H14Cl2N6; H-NMR (400 MHz, CDCl₃) 8.80 (s, 1H), 7.953 (d, J=8.277Hz, 2H), 7.750 (d, J=8.093 Hz, 2H), 7.593 (d, J=9.533 Hz, 1H), 7.234 (d,J=9.551 Hz, 1H), 6.545 (s, 1H), 5.257 (s, NH), 5.03 (d, J=5.498 Hz, 2H,D, CH2), 2.311 (s, 6H, D, 2CH3) ppm.

Example 1624-chloro-N-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-6-methylpyrimidin-2-amine(162)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from6-chloro-3-(chloromethyl)-2-(4-fluorophenyl)imidazo[1,2-a]pyridinehydrochloride and 4-chloro-6-methylpyrimidin-2-amine. m/e+402.0, 404.0for C19H14Cl2FN5.

Example 1636-Methyl-3-phenylsulfanylmethyl-2-p-tolyl-imidazo[1,2-a]pyridine (163)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand benzenethiol. m/e⁺345 for C₂₂H₂₁N₂ (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ7.81 (s, 1H), 7.59 (d, J=8.0 Hz, 2H), 7.54 (d, J=9.1 Hz, 1H), 7.35 (d,J=1.8 Hz, 2H), 7.32 (m, 5H), 7.07 (d, J=9.1 Hz, 1H), 4.54 (s, 2H), 2.39(s, 3H), 2.34 (s, 3H) ppm.

Example 1644,6-difluoro-N-((2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine(164)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-2-phenylimidazo[1,2-a]pyridine hydrochloride and4,6-difluoropyrimidin-2-amine. (0.10 g, 17% yield), M/e⁺ 338.2 forC₁₈H₁₃F₂N₅ (M+H)⁺

Example 165

N-((6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)-6-methoxypyridazin-3-amine(165)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridinehydrochloride and 6-methoxypyridazin-3-amine compound. M/e⁺ 366 forC₁₉H₁₇ClN₅O (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃) δ 8.16 (t, J=0.7 Hz, 1H),7.68 (dd, J=8.4, 1.4 Hz, 2H), 7.52 (d, J=9.5 Hz, 1H), 7.39 (m, 3H), 7.16(dd, J=9.5, 1.8 Hz, 1H), 6.84 (q, J=9.5 Hz, 2H), 5.07 (d, J=4.7 Hz, 2H),4.06 (s, 3H), 1.62 (bs, 1H) ppm.

Example 1664,6-difluoro-N-((2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine(166)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridinehydrochloride and 4,6-difluoropyrimidin-2-amine. (0.23 g, 39% yield),M/e⁺ 370.1 for C₁₉H₁₄F₃N₅ (M+H)⁺.

Example 167

N-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4,6-difluoropyrimidin-2-amine(167)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochlorideand 4,6-difluoropyrimidin-2-amine. (0.100 g, 34% yield); ¹H-NMR (300MHz, CDCl₃, δ) 8.08 (d, J=6.9 Hz, 1H), 7.64-7.85 (m, 3H) 7.37-7.33 (m,2H), 7.25-7.20 (m, 1H), 6.85-6.80 (m, 1H), 6.07 (t, J=9.3 Hz, 1H),5.86-5.85 (m, 1H), 5.99 (d, J=5.4 Hz, 2H).

Example 168N-((6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)-4,6-difluoropyrimidin-2-amine(168)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from6-chloro-3-(chloromethyl)-2-phenylimidazo[1,2-a]pyridine hydrochlorideand 4,6-difluoropyrimidin-2-amine. ((0.26 g, 43% yield), M/e⁺ 372.2 forC₁₈H₁₂ClF₂N₅ (M+H)⁺.

Example 169N-((6-Chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4,6-difluoropyrimidin-2-amine(169)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from6-chloro-3-(chloromethyl)-2-(4-fluorophenyl)imidazo[1,2-a]pyridinehydrochloride and 4,6-difluoropyrimidin-2-amine. (0.42 g, 45% yield).M/e⁺ 390.2 for C₁₈H₁₁ClF₃N₅ (M+H)⁺.

Example 1704-chloro-N-((6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-6-methylpyrimidin-2-amine(170)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride and 4-chloro-6-methylpyrimidin-2-amine. ¹H-NMR (400 MHz,CDCl₃) δ 8.56 (s, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.55 (d, J=9.5 Hz, 1H),7.40 (d, J=8.5 Hz, 2H), 7.18 (dd, J=1.8, 9.5 Hz, 1H), 6.55 (s, 1H), 5.59(broad, 1H), 4.99 (d, J=5.6 Hz, 2H), 2.34 (s, 3H); m/e⁺ 419 forC19H14Cl3N5 [M+H]⁺.

Example 171(6,8-Dichloro-2-p-tolyl-imidazo[1,2-a]pyridin-3-ylmethyl)-(1H-imidazol-2-yl)-amine(171)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from6,8-dichloro-3-(chloromethyl)-2-p-tolylimidazo[1,2-a]pyridinehydrochloride and 1H-imidazol-2-amine. m/e⁺ 372 for C₁₈H₁₆Cl₂N₅ [M+H]⁺;¹H-NMR (300 MHz, CDCl₃) δ 8.10 (s, 1H), 7.27 (m, 4H), 6.92 (d, J=6.6 Hz,2H), 6.76 (s, 2H), 4.67 (s, 2H), 4.50 (bs, 1H), 2.31 (s, 3H) ppm.

Example 172(6,8-Dichloro-2-p-tolyl-imidazo[1,2-a]pyridin-3-ylmethyl)-(4,6-dimethyl-pyrimidin-2-yl)-amine(172)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from6,8-dichloro-3-(chloromethyl)-2-p-tolylimidazo[1,2-a]pyridinehydrochloride and 4,6-dimethylpyrimidin-2-amine. m/e⁺ 412 forC₂₁H₂₀Cl₂N₅ [M+H]⁺; ¹H-NMR (400 MHz, CDCl₃) δ 8.85 (d, J=1.4 Hz, 1H),7.64 (d, J=8.0 Hz, 2H), 7.48 (d, J=7.7 Hz, 1H), 7.25 (d, J=8.0 Hz, 2H),7.14 (d, J=7.7 Hz, 1H), 6.41 (s, 1H), 5.02 (s, 2H), 2.40 (s, 3H), 2.36(s, 3H), 2.33 (s, 3H) ppm.

Example 1732-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methoxy)isoindoline-1,3-dione(173)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 2-hydroxyisoindoline-1,3-dione. m/e⁺ 398.3 for C₂₄H₂₀N₃O₃ (M+H)⁺;¹H-NMR (400 MHz, CDCl₃, δ) 8.542 (s, 1H), 7.8-7.6 (m, 7H), 7.26-7.22 (m,3H), 5.523 (s, 2H, D, CH₂), 2.475 (s, 3H, D, CH₃), 2.351 (s, 3H, D, CH₃)ppm.

Example 1741-((6-methyl-2-p-tolylH-imidazo[1,2-a]pyridin-3-yl)methoxy)-1H-benzo[d][1,2,3]triazole(174)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 1H-benzo[d][1,2,3]triazol-1-ol. m/e⁺ 370.5 for C₂₂H₂₀N₅O (M+H)⁺;¹H-NMR (400 MHz, CDCl₃, δ) 8.030 (s, 1H), 7.91 (d, J=8.798 Hz, 1H), 7.63(d, J=7.698 Hz, 2H), 7.56 (d, J=9.164 Hz, 1H), 7.35 (d, J=8.065 Hz, 2H),7.28 (m, 2H), 7.12 (d, J=9.165 Hz, 1H), 6.72 (dd, J₁=7.331 Hz, J=5.865Hz, 1H), 6.007 (s, 2H, D, CH₂), 2.456 (s, 3H, D, CH₃), 2.339 (s, 3H, D,CH₃) ppm.

Example 1756-Methyl-3-(pyridin-3-yloxymethyl)-2-p-tolyl-imidazo[1,2-a]pyridine(175)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 1H-benzo[d][1,2,3]triazol-1-ol. and pyridin-3-ol. m/e⁺ 350 forC₂₁H₂₀N₃O [M+H]⁺; ¹H-NMR (400 MHz, CDCl₃) δ 8.38 (d, J=1.8 Hz, 1H), 8.27(dd, J=1.8, 4.4 Hz, 1H), 8.21 (d, J=2.5 Hz, 1H), 8.02 (d, J=4.4 Hz, 1H),7.91 (s, 1H), 7.59 (dd, J=1.4, 8.0 Hz, 2H), 7.23 (d, J=1.4, 8.0 Hz, 2H),7.15 (m, 2H), 5.42 (s, 2H), 2.36 (s, 3H), 2.35 (s, 3H) ppm.

Example 1763-((4-methyl-4H-1,2,4-triazol-3-ylthio)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine(176)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 4-methyl-4H-1,2,4-triazole-3-thiol. m/e⁺ 350 for C₁₉H₂₀N₅S [M+H]⁺;¹H-NMR (400 MHz, CDCl₃, δ) 8.55 (s, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.79(s, 1H), 7.67 (d, J=9.1 Hz, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.16 (d, J=9.1Hz, 1H), 5.77 (s, 2H, D, CH₂), 3.65 (s, 3H, D, CH₃), 2.41 (s, 3H, D,CH₃), 2.36 (s, 3H, D, CH₃) ppm.

Example 1776-Methyl-2-p-tolyl-3-(1H-[1,2,4]triazol-3-ylsulfanylmethyl)-imidazo[1,2-a]pyridine(177)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 1H-1,2,4-triazole-3-thiol. m/e+336 for C18H18N5S (M+H)+; ¹H NMR (400MHz, CDCl₃) δ□ 8.10 (s, 1H), 7.90 (s, 1H), 7.57 (m, 3H), 7.21 (d, J=7.7Hz, 2H), 7.11 (dd, J=1.1, 9.1 Hz, 1H), 4.78 (s, 2H), 2.36 (s, 3H), 2.33(s, 3H) 0.90 (bs, 1H) ppm.

Example 1786-Methyl-3-(thiophen-2-ylsulfanylmethyl)-2-p-tolyl-imidazo[1,2-a]pyridine(178)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand thiophene-2-thiol. m/e⁺ 351 for C₂₀H₁₉N₂S₂ [M+H]⁺; ¹H-NMR (400 MHz,CDCl₃) δ 7.75 (s, 1H), 7.53 (s, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.29 (dd,J=1.1, 5.1 Hz, 1H), 7.20 (d, J=8.0 Hz, 2H), 7.04 (dd, J=1.4, 9.1 Hz,1H), 6.95 (dd, J=1.1, 3.6 Hz, 1H), 6.87 (dd, J=3.6, 5.5 Hz, 1H), 4.40(s, 2H), 2.37 (s, 3H), 2.33 (s, 3H) ppm; ¹³C-NMR (100 MHz, CDCl₃, δ)145.528, 144.436, 137.718, 135.777, 132.167, 131.485, 131.098, 129.437,128.391, 128.057, 127.944, 122.074, 121.711, 117.032, 114.621, 33.849,21.527, 18.699 ppm.

Example 1706-Methyl-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-2-p-tolyl-imidazo[1,2-a]pyridine(179)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 5-methyl-1,3,4-thiadiazole-2-thiol. m/e⁺ 367 for C₁₉H₁₉N₄S₂ [M+H]⁺;¹H-NMR (400 MHz, CDCl₃) δ 8.27 (s, 1H), 7.86 (d, J=8.0 Hz, 2H), 7.55 (d,J=9.1 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.09 (dd, J=1.4, 9.1 Hz, 1H),5.83 (s, 2H), 2.40 (s, 3H), 2.37 (s, 3H), 2.33 (s, 3H) ppm; ¹³C-NMR (100MHz, CDCl₃, δ) 186.983, 156.637, 146.840, 144.588, 138.165, 131.265,129.597, 128.800, 128.649, 122.931, 122.787, 116.971, 113.923, 44.131,21.557, 18.638, 16.606 ppm.

Example 1806-Methyl-3-([1,3,4]thiadiazol-2-ylsulfanylmethyl)-2-p-tolyl-imidazo[1,2-a]pyridine(180)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 1,3,4-thiadiazole-2-thiol. m/e⁺ 353 for C₁₈H₁₇N₄S₂ [M+H]⁺; ¹H-NMR(300 MHz, CDCl₃) δ 8.22 (d, J=10.2 Hz, 2H), 7.82 (dd, J=1.8, 6.3 Hz,2H), 7.57 (d, J=9 Hz, 1H), 7.27 (d, J=9 Hz, 2H), 7.12 (dd, J=1.5, 9.0Hz, 1H), 5.91 (s, 2H), 2.41 (s, 3H), 2.34 (s, 3H) ppm.

Example 1813-((4,6-dimethylpyrimidin-2-ylthio)methyl)-6-methyl-2-p-tolylH-imidazo[1,2-a]pyridine(181)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochlorideand 4,6-dimethylpyrimidine-2-thiol. m/e⁺ 375.3 for C₂₂H₂₃N₄S [M+H]⁺;¹H-NMR (400 MHz, CDCl₃) δ 8.00 (s, 1H), 7.77 (d, J=8 Hz, 2H), 7.54 (d,J=9.2 Hz, 1H), 7.27 (d, J=8 Hz, 2H), 7.05 (d, J=9.2 Hz, 1H), 6.74 (s,1H), 4.95 (s, 2H), 2.40 (s, 6H), 2.39 (s, 3H), 2.31 (s, 3H) ppm; ¹³C-NMR(100 MHz, CDCl₃, δ) 170.64, 167.50, 144.89, 144.50, 137.71, 131.70,129.57, 128.53, 127.88, 122.13, 122.07, 116.99, 116.36, 114.08, 26.19,24.06, 21.52, 18.68 ppm.

Example 1824,6-Difluoro-N-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine(182)

The title compound was prepared according to Method A and theexperimentals described for compound 139 from3-(chloromethyl)-6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridinehydrochloride and 4,6-difluoropyrimidin-2-amine. (0.35 g, 39% yield).M/e⁺ 374.2 for C₁₈H₁₁F₄N₅ (M+H)⁺.

General Procedure for Chloro Displacement with Nucleophiles (RONa, RSNaor R₃R₄NH)

Starting material and 5-10 eq of ROH or RSH (in THF, with 1-2 eq of NaH)or R₁R₂NH (neat or in t-BuOH) was heated from 65° C. to 95° C. until thereaction was completed. The mixture was diluted with ethyl acetate andthe resulting mixture was washed with saturated NaHCO₃ and brine, driedover Na₂SO₄ and concentrated by evaporation. The crude product waspurified by silica gel chromatography (methanol/methylene chloridegradient) to obtain the desired product)

Example 183(R)—N-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-(1-methylpyrrolidin-3-yloxy)pyrimidin-2-amine(183)

To a solution of (R)-1-methylpyrrolidin-3-ol (66 mg, 0.65 mmol) in THF(3 ml) was added NaH (25 mg, 65% in mineral oil). The mixture wasstirred for 30 min and4-chloro-N-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine(50 mg, 0.13 mmol) was added. The mixture was heated from 65 to 95° C.until the reaction was completed. The mixture was diluted with ethylacetate and the resulting mixture was washed with saturated NaHCO₃ andbrine, dried over Na₂SO₄ and concentrated by evaporation. The crudeproduct was purified by silica gel chromatography (methanol/methylenechloride gradient) to obtain the desired product. ¹H-NMR (CDCl₃, 400MHz, δ) 8.23 (s, 1H), 7.69 (m, 2H), 7.52 (d, J=9.5 Hz, 1H), 7.12 (m,3H), 5.97 (s, 1H), 5.36 (s, 1H), 4.96 (d, J=4.7 Hz, 2H), 2.80 (m, 3H),2.68 (m, 1H), 2.34 (s, 3H), 2.25 (m, 2H), 1.96 (m, 1H) ppm; m/e 453(M+H)⁺.

Example 184(S)—N-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-(1-methylpyrrolidin-3-yloxy)pyrimidin-2-amine(184)

The title compound was prepared in the same fashion as that describedfor compound 183 from4-chloro-N-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amineand (S)-1-methylpyrrolidin-3-ol. ¹H-NMR (CDCl₃, 400 MHz, δ) 8.20 (s,1H), 7.65 (m, 1H), 7.50 (d, J=9.5 Hz, 1H), 9.10 (m, 3H), 5.93 (s, 1H),5.34 (s, 1H), 4.93 (d, J=4.9 Hz, 2H), 2.75 (m, 4H), 2.33 (s, 3H), 2.25(m, 2H), 1.95 (m, 1H) ppm; m/e 453 (M+H)⁺.

Example 185N-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-2-(2-(methylamino)ethoxy)pyrimidin-4-amine(185)

The title compound was prepared in the same fashion as that describedfor compound 183 from2-chloro-N-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-4-amineand 2-(methylamino)ethanol. M/e⁺ 409 for C₂₁H₂₂ClN₆O (M+H)⁺; ¹H-NMR (400MHz, CD₃OD) δ 8.61 (s, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.68 (d, J=6.2 Hz,1H), 7.50 (t, J=7.3 Hz, 2H), 7.43 (d, J=7.3 Hz, 1H), 7.39 (m, 1H), 5.84(d, J=6.2 Hz, 2H), 5.08 (d, J=8.8 Hz, 2H), 3.74 (m, 2H), 3.17 (s, 3H)ppm.

Example 1862-(4-chlorophenyl)-3-((6-(pyrrolidin-3-yloxy)pyrazin-2-yl)methyl)imidazo[1,2-a]pyridine(186)

The title compound was prepared according to the experimental forcompound 183 from2-(4-chlorophenyl)-3-((6-chloropyrazin-2-yl)methyl)imidazo[1,2-a]pyridineand pyrrolidin-3-ol. M/e⁺ 406 for C₂₂H₂₁ClN₅O (M+H)⁺; ¹H-NMR (400 MHz,CDCl₃) δ 8.20 (d, J=6.9 Hz, 1H), 7.91 (dd, J=6.6, 1.8 Hz, 2H), 7.75 (d,J=8.4 Hz, 2H), 7.62 (d, J=9.1 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.20 (m,1H), 6.79 (td, J=6.9, 1.1 Hz, 1H), 4.59 (s, 1H), 4.35 (s, 2H), 3.54 (m,3H), 2.09 (m, 2H), 1.55 (s, 1H) ppm

Example 1871-(2-((6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)methylamino)pyrimidin-4-yl)-4-methylpiperidin-4-ol(187)

A mixture of4-chloro-N-((6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine(50 mg, 0.135 mmol) and 4-methylpiperidin-4-ol (200 mg, 1.74 mmol) int-BuOH (0.5 ml) was heated 95° C. until the reaction was completed. Themixture was diluted with ethyl acetate and the resulting mixture waswashed with saturated NaHCO₃ and brine, dried over Na₂SO₄ andconcentrated by evaporation. The crude product was purified by silicagel chromatography (methanol/methylene chloride gradient) to titlecompound. M/e⁺ 449 for C₂₄H₂₆ClN₆O (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃) δ8.47 (s, 1H), 7.89 (d, J=5.8 Hz, 1H), 7.76 (d, J=6.9 Hz, 2H), 7.57 (d,J=9.5 Hz, 1H), 7.47 (m, 3H), 7.39 (d, J=7.7 Hz, 1H), 7.16 (dd, J=9.5,1.8 Hz, 1H), 5.99 (d, J=6.2 Hz, 1H), 5.05 (d, J=5.5 Hz, 2H), 5.00 (bs,1H), 4.00 (m, 2H), 3.40 (m, 2H), 1.62 (m, 4H), 1.29 (s, 3H) ppm.

Example 188(R)-(1-(2-((6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)methylamino)pyrimidin-4-yl)pyrrolidin-2-yl)methanol(188)

The title compound was prepared in the same fashion as that describedfor compound 187 from4-chloro-N-((6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amineand (R)-pyrrolidin-2-ylmethanol. m/e 435 (M+H)⁺.

Example 1891-(2-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methylamino)pyrimidin-4-yl)pyrrolidin-3-ol(189)

The title compound was prepared in the same fashion as that describedfor compound 187 fromN-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amineand pyrrolidin-3-ol. ¹H-NMR (CDCl₃, 400 MHz, δ) 8.72 (d, J=11.6 Hz, 1H),8.32 (s, 1H), 7.78 (dd, J=5.7, 8.3 Hz, 2H), 7.66 (s, 1H), 7.61 (d, J=9.6Hz, 2H), 7.41 (d, J=9.6 Hz, 1H), 7.26 (t, J=8.7 Hz, 2H), 6.13 (dd,J=6.3, 21.2 Hz, 1H), 5.10 (s, 2H), 4.88 (1H), 4.48 (d, J=36.5 Hz, 1H),3.60 (m, 1H), 3.52 (m, 1H), 3.42 (m, 1H), 2.42 (m, 2H) ppm; m/e 439(M+H)⁺.

Example 190N1-(6-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrazin-2-yl)-N2,N2-dimethylethane-1,2-diamine(190)

The title compound was prepared in the same fashion as that describedfor compound 187 from2-(4-chlorophenyl)-3-((6-chloropyrazin-2-yl)methyl)imidazo[1,2-a]pyridineand N¹,N¹-dimethylethane-1,2-diamine. M/e⁺ 407 for C₂₂H₂₄ClN₆ (M+H)⁺;¹H-NMR (400 MHz, CDCl₃) δ 8.12 (d, J=6.9 Hz, 1H), 7.85 (d, J=8.8 Hz,2H), 7.78 (s, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.20(m, 1H), 6.78 (m, 1H), 5.30 (s, 1H), 4.34 (s, 2H), 3.29 (q, J=5.5 Hz,2H), 2.46 (t, J=5.5 Hz, 2H), 2.21 (s, 6H) ppm.

Example 1911-(6-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrazin-2-yl)pyrrolidin-3-ol(191)

The title compound was prepared according to the experimental forcompound 187 from2-(4-chlorophenyl)-3-((6-chloropyrazin-2-yl)methyl)imidazo[1,2-a]pyridineand pyrrolidin-3-ol. M/e⁺ 406 for C₂₂H₂₁ClN₅O (M+H)⁺; ¹H-NMR (400 MHz,CDCl₃) δ 8.20 (d, J=6.2 Hz, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.71 (d, J=10.6Hz, 2H), 7.59 (dd, J=9.1, 0.7 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.16 (m,1H), 6.77 (t, J=6.9 Hz, 1H), 4.56 (s, 1H), 4.32 (s, 2H), 4.06 (m, 1H),3.53 (m, 3H), 3.00 (bs, 1H), 2.04 (m, 2H) ppm.

Example 1922-((6-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrazin-2-yl)(methyl)amino)ethanol(192)

The title compound was prepared according to the experimental forcompound 187 from2-(4-chlorophenyl)-3-((6-chloropyrazin-2-yl)methyl)imidazo[1,2-a]pyridineand 2-(methylamino)ethanol. M/e⁺ 394 for C₂₁H₂₁ClN₅O (M+H)⁺; ¹H-NMR (400MHz, CDCl₃) δ 8.06 (d, J=6.6 Hz, 1H), 7.89 (s, 1H), 7.78 (d, J=8.4 Hz,2H), 7.70 (s, 1H), 7.60 (dd, J=8.4, 0.7 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H),7.17 (m, 1H), 6.77 (t, J=6.9 Hz, 1H), 4.34 (s, 2H), 3.64 (t, J=5.1 Hz,2H), 3.54 (t, J=5.1 Hz, 2H), 3.05 (s, 3H) ppm.

Example 1932-(4-chlorophenyl)-3-((6-(2-methylhydrazinyl)pyrazin-2-yl)methyl)imidazo[1,2-a]pyridine(193)

The title compound was prepared according to the experimental forcompound 187 from2-(4-chlorophenyl)-3-((6-chloropyrazin-2-yl)methyl)imidazo[1,2-a]pyridineand methylhydrazine. M/e⁺ 365 for C₁₉H₁₈ClN₆ (M+H)⁺; ¹H-NMR (400 MHz,CDCl₃) δ 8.41 (s, 1H), 8.12 (d, J=6.9 Hz, 1H), 7.83 (d, J=8.4 Hz, 2H),7.73 (s, 1H), 7.63 (d, J=9.1 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.19 (m,1H), 6.78 (t, J=6.9 Hz, 1H), 4.36 (s, 2H), 3.88 (bs, 2H), 3.18 (s, 3H)ppm.

Example 194 Tert-butyl2-(2-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methylamino)pyrimidin-4-yl)pyrrolidine-1-carboxylate(194)

To a solution of6-chloro-3-(chloromethyl)-2-(4-fluorophenyl)imidazo[1,2-a]pyridinehydrochloride (100 mg, 0.35 mmol) in acetonitrile (25 mL) was addedtert-butyl 2-(2-aminopyrimidin-4-yl)pyrrolidine-1-carboxylate (preparedaccording to the procedures described in WO 2007/09117 A1)(190 mg, 0.71mmol) and freshly ground potassium carbonate (150 mg, 1.1 mmol) and thereaction mixture was heated to 60° C. for 16 h. After this time thereaction mixture was cooled to room temperature, diluted with ethylacetate (20 mL) and washed with brine (2×20 mL). The organic layer wasseparated, dried over Na₂SO₄, concentrated and purified by columnchromatography (methanol/methylene chloride) to afford the desiredproduct. (0.10 g, 54% yield). M/e⁺ 523.1 for C₂₇H₂₈ClFN₆O₂ (M+H)⁺,¹H-NMR (500 MHz, CDCl₃, δ) 8.45 (d, J=1.0 Hz, 1H), 8.28 (s, 1H),7.77-7.74 (m, 2H), 7.58 (d, J=9.5 Hz, 1H), 7.20-7.15 (m, 3H), 6.55 (d,J=5.0 Hz, 1H), 5.18 (s, 1H), 5.07-5.01 (m, 2H), 4.62 (s, 1H), 3.61-3.52(m, 2H), 2.34 (m, 1H), 1.98-1.94 (m, 1H), 1.91-1.86 (m, 2H), 1.26 (s,9H) and signals due to a minor tautomer (ca. 44%): 4.77 (d, J=5.0 Hz),1.46 (s).

Example 195N-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-(pyrrolidin-2-yl)pyrimidin-2-amine(195)

To a solution of tert-butyl2-(2-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methylamino)pyrimidin-4-yl)pyrrolidine-1-carboxylate(64 mg, 120 mmol) in methylene chloride (5 mL) was added trifluoroaceticacid (2 mL) and the reaction was stirred at room temperature for 16 h.After this time the reaction was concentrated and purified by reversephase preparatory HPLC (acetonitrile/water gradient) to afford thedesired product. (0.045 g, 88% yield). M/e⁺ 423.1 for C₂₂H₂₀ClFN₆(M+H)⁺, ¹H-NMR (500 mHz, CDCl₃, δ), 8.45 (d, J=1.0 Hz, 1H), 8.29 (d,J=5.5 Hz, 1H), 7.77-7.75 (m, 2H), 7.58 (d, J=9.5 Hz, 1H), 7.20-7.15 (m,3H), 6.72 (d, J=5.0 Hz, 1H), 5.06 (d, J=6.0 Hz, 2H), 4.13 (t, J=14.5 Hz,1H), 3.19-3.14 (m, 1H), 3.06-3.01 (m, 1H), 2.26-2.22 (m, 1H), 1.88-1.72(m, 3H).

Example 1964-((ethylamino)methyl)-N-((2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine(196)

To a suspension of2-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methylamino)pyrimidine-4-carbaldehyde(110 mg, 0.29 mmol) in CH₂Cl₂ (5 mL) was added acetic acid (0.5 mL)until the reaction became clear. Ethylamine (0.87 mmol, 3.0 eq) andNa(OAc)₃BH (0.58 mmol, 2.0 eq) were added and the reaction mixture wasstirred for 18 h at room temperature. After this time the reaction wasdiluted with CH₂Cl₂ (20 mL) and quenched by the addition of satd. aq.NaHCO₃ (10 mL). After stirring for 10 min the layers were separated andthe organic layer was dried over Na₂SO₄, filtered, concentrated andpurified by reverse phase preparatory HPLC (silica gel,acetonitrile/water w/0.05% TFA) to afford the desired product. (0.060 g,37% yield). M/e⁺ 411.1 for C₂₁H₂₀ClFN₆ (M+H)⁺; ¹H-NMR (500 MHz, CDCl₃,δ) 8.48 (d, J=1.5 Hz, 1H), 8.29 (d, J=5.0 Hz, 1H), 7.78-7.75 (m, 2H),7.58 (d, J=9.5 Hz, 1H), 7.21-7.15 (m, 3H), 6.70 (d, J=5.5 Hz, 1H), 5.24(br s, 1H), 5.05 (d, J=5.5 Hz, 2H), 3.77 (s, 2H), 2.72 (q, J=7.5 Hz,2H), 1.15 (t, J=7.5 Hz, 3H).

Example 1974-((ethylmethyl)amino)methyl)-N-((2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine(197)

The title compound was prepared in the same fashion as that describedfor compound 196 from2-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methylamino)pyrimidine-4-carbaldehydeand N-methylethanamine. (0.068 g, 40% yield). M/e⁺ 425.1 for C₂₂H₂₂ClFN₆(M+H)⁺; ¹H-NMR (500 MHz, CDCl₃, δ) 8.55 (s, 1H), 8.30 (d, J=5.0 Hz, 1H),7.78-7.75 (m, 2H), 7.57 (d, J=9.5 Hz, 1H), 7.20-7.15 (m, 3H), 6.83 (d,J=5.0 Hz, 1H), 5.26 (br s, 1H), 5.05 (d, J=6.0 Hz, 2H), 3.48 (s, 2H),2.51 (q, J=7.0 Hz, 2H), 2.28 (s, 3H), 1.11 (t, J=7.0 Hz, 3H)

Example 198N-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-(pyrrolidin-1-ylmethyl)pyrimidin-2-amine(198)

The title compound was prepared in the same fashion as that describedfor compound 196 from2-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methylamino)pyrimidine-4-carbaldehydeand pyrrolidine. (0.040 g, 33% yield). M/e⁺ 437.1 for C₂₃H₂₂ClFN₆(M+H)⁺; ¹H-NMR (500 MHz, CDCl₃, δ) 8.54 (s, 1H), 8.30 (d, J=5.0 Hz, 1H),7.77-7.75 (m, 2H), 7.57 (dd, J=9.5. 0.5 Hz, 1H), 7.20-7.15 (m, 3H), 6.81(d, J=5.0 Hz, 1H), 5.32-5.26 (m, 1H), 5.05 (d, J=5.5 Hz, 2H), 3.64 (s,2H), 2.64 (br s, 4H), 1.84 (br s, 4H).

Example 1996-fluoro-2-(4-fluorophenyl)-3-((1-methyl-1H-imidazol-2-yl)methyl)imidazo[1,2-a]pyridine(199)

Step 1: To a solution of 1-methyl-1H-imidazole (2.6 eq) in THF (5 mL) at−78° C. was added n-butyllithium (2.5 M) dropwise. After 15 min, thesolution was warmed to 0° C. for 15 min. The solution was cooled back to−78° C. and the6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde (1 eq)was added portion wise as a solid. The mixture was warmed to roomtemperature and stirred overnight, quenched with saturated NaHCO₃ (15mL) and the solvents were removed under vacuum. The residue wastriturated with diethyl ether or acetonitrile and the resulting solidwas collected by filtration and washed with ether and water. The crudeproduct was purified by chromatographed (silica gel, heptanes/ethylacetate). m/e⁺ 341 (M+H)⁺.

Step 2: A Teflon-capped high-pressure glass bottle was charged with(6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)(1-methyl-1H-imidazol-2-yl)methanol(2.2 g, 6.4 mmoles, 1.0 eq.), dry CH₂Cl₂ (60 ml) and solid P₂I₄ (7.3 g,12.9 mmoles, 2.0 eq.). The bottle was flushed with N₂ and heated at 40°C. for 60 hours. The reaction was quenched with NaHCO₃ (200 ml, 1.0 M inwater), extracted (3×200 ml CH₂Cl₂), the organic layer was dried withMgSO₄ and concentrated on rotary evaporator. The crude residue waspurified by flash chromatography (30%->70% gradient of 10% MeOH/90%EtOAc in hexanes on a 330 g silica gel column). The purified product wascrystallized from hot EtOAc. Yield: 1.1 g (53%). Repeatedcrystallization provided additional 0.7 g (34%) having equal purity.(0.19 g, 53% yield). M/e⁺ 325 for C₁₈H₁₅F₂N₄ (M+H)⁺; ¹H-NMR (400 MHz,CDCl₃) δ 8.35 (d, J=1.8 Hz, 1H), 7.68 (dd, J=7.7, 5.5 Hz, 2H), 7.57 (dd,J=9.9, 5.1 Hz, 1H), 7.25 (d, J=1.1 Hz, 1H), 7.18 (t, J=8.4 Hz, 1H), 7.11(t, J=7.7 Hz, 1H), 6.92 (s, 1H), 6.74 (s, 1H), 4.50 (s, 2H), 3.19 (s,3H) ppm.

Example 2006-fluoro-2-(4-fluorophenyl)-3-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)imidazo[1,2-a]pyridine(200)

The tilte compound was prepared according to Method C and theexperimentals described for compound 199 from6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and1-methyl-1H-1,2,4-triazole. (0.19 g, 53% yield). M/e+326.2 forC₁₇H₁₄F₂N₅ (M+H)⁺; ¹H-NMR (500 MHz, DMSO-d6, δ) 8.55 (dd, J=5.0, 2.0 Hz,1H), 7.72-7.68 (m, 4H), 7.40-7.36 (m, 1H), 7.31-7.27 (m, 2H), 4.64 (s,2H), 3.86 (s, 3H).

Example 2013-((6-fluoro-2-(4-fluoropnyl)imidazo[1,2-a]pyridin-3-yl)methyl)-5-methyl-1,2,4-oxadiazole(201)

The tilte compound was prepared according to Method C and theexperimentals described for compound 199 from6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and5-methyl-1,2,4-oxadiazole. M/e⁺ 327 for C₁₇H₁₃F₂N₄O (M+H)⁺; ¹H-NMR (400MHz, CDCl₃) δ 8.22 (4.0, 2.2 Hz, 1H), 7.90 (dd, J=8.8, 5.5 Hz, 2H), 7.63(dd, J=9.9, 5.1 Hz, 1H), 7.17 (m, 3H), 4.38 (s, 2H), 2.58 (s, 3H) ppm.

Example 2023-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-5-methyl-1,2,4-oxadiazole(202)

The tilte compound was prepared according to Method C and theexperimentals described for compound 199 from2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and5-methyl-1,2,4-oxadiazole. M/e⁺ 325 for C₁₇H₁₄ClN₄O (M+H)⁺; ¹H-NMR (400MHz, CDCl₃) δ 8.22 (d, J=6.9 Hz, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.66 (d,J=8.8 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.23 (m, 1H), 6.88 (t, J=6.9 Hz,1H), 4.42 (d, J=0.7 Hz, 2H), 2.56 (s, 3H) ppm.

Example 2032-((2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)methyl)-5-methyl-1,3,4-oxadiazole(203)

The tilte compound was prepared according to Method C and theexperimentals described for compound 199 from2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridine-3-carbaldehyde and2-methyl-1,3,4-oxadiazole. M/e⁺ 339 for C₁₈H₁₆ClN₄O (M+H)⁺; ¹H-NMR (400MHz, CDCl₃) δ 7.95 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.56 (d, J=9.1 Hz,1H), 7.45 (d, J=8.4 Hz, 2H), 7.10 (dd, J=9.1, 1.4 Hz, 1H), 4.54 (s, 2H),2.49 (s, 3H), 2.35 (s, 3H) ppm.

Example 2042-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-5-methyl-1,3,4-oxadiazole(204)

The tilte compound was prepared according to Method C and theexperimentals described for compound 199 from2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and2-methyl-1,3,4-oxadiazole. M/e⁺ 325 for C₁₇H₁₄ClN₄O (M+H)⁺; ¹H-NMR (400MHz, CDCl₃) δ 8.22 (d, J=6.6 Hz, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.67 (d,J=9.1 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.27 (t, J=6.9 Hz, 1H), 6.91 (d,J=6.6 Hz, 1H), 4.58 (s, 2H), 2.50 (s, 3H) ppm.

Example 2052-((6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)-5-methyl-1,3,4-oxadiazole(205)

The tilte compound was prepared according to Method C and theexperimentals described for compound 199 from6-chloro-2-phenylimidazo[1,2-a]pyridine-3-carbaldehyde and2-methyl-1,3,4-oxadiazole. M/e⁺ 325 for C₁₇H₁₄ClN₄O (M+H)⁺; ¹H-NMR (400MHz, CDCl₃) δ 8.25 (d, J=1.4 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.61 (d,J=9.5 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.43 (d, J=7.3 Hz, 1H), 7.22 (dd,J=9.5, 1.8 Hz, 1H), 4.58 (s, 2H), 2.52 (s, 3H) ppm.

Example 2062-(4-chlorophenyl)-3-((1-methyl-1H-imidazol-2-yl)methyl)imidazo[1,2-a]pyridine(206)

The tilte compound was prepared according to Method C and theexperimentals described for compound 199 from2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and1-methyl-1H-imidazole. (21.6 mg, 19% yield). M/e⁺ 323.1 for C₁₈H₁₅ClN₄(M+H)⁺; ¹H-NMR (300 MHz, DMSO, 6) 8.25 (d, J=6.9 Hz, 1H), 7.75 (dd,J=8.7, 2.1 Hz, 2H), 7.61 (d, J=9.0 Hz, 1H), 7.51 (dd, J=8.4, 1.8 Hz,2H), 7.28 (t, J=2.1 Hz, 1H), 7.08 (d, J=0.9 Hz, 1H), 6.91 (t, J=6.9 Hz,1H), 6.68 (d, J=0.9 Hz, 1H), 4.53 (s, 2H), 3.58 (s, 3H).

Example 2072-(4-Chlorophenyl)-3-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)imidazo[1,2-a]pyridine(207)

The tilte compound was prepared according to Method C and theexperimentals described for compound 199 from2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and1-methyl-1H-1,2,4-triazole. (0.22 g, 89% yield). M/e⁺ 324.1 forC₁₇H₁₄ClN₅ (M+H)⁺; ¹H-NMR (300 MHz, DMSO-d₆, 6) 8.26 (d, J=6.9 Hz, 1H),7.74-7.70 (m, 3H), 7.65-7.61 (m, 1H), 7.54-7.51 (m, 2H), 7.33-7.28 (m,1H), 6.93 (td, J=6.8, 1.2 Hz, 1H), 4.68 (s, 2H), 3.87 (s, 3H).

Example 2082-(4-chlorophenyl)-3-((1-vinyl-1H-imidazol-2-yl)methyl)imidazo[1,2-a]pyridine(208)

The tilte compound was prepared according to Method C and theexperimentals described for compound 199 from2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and1-vinyl-1H-imidazole. (34 mg, 18%). m/e⁺=335 (M+H⁺). ¹H-NMR (400 MHz,CDCl₃, δ): 8.28 (d, 1H, D, J=7.0 Hz), 7.66 (d, 2H, D, J=10.2 Hz), 7.61(d, 1H, D, J=9.2 Hz), 7.46 (d, 2H, D, J=8.5 Hz), 7.19 (t, 1H, D, J=7.9Hz), 7.08 (d, 1H), 6.96 (d, 1H), 6.80 (t, 1H, D, J=7.0 Hz), 6.46 (m,1H), 5.03 (m, 1H), 4.62 (m, 1H), 4.56 (s, 2H).

Example 2096-fluoro-2-(4-fluorophenyl)-3-((1-vinyl-1H-1,2,4-triazol-5-yl)methyl)imidazo[1,2-a]pyridine(209)

The tilte compound was prepared according to Method C and theexperimentals described for compound 199 from6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and1-vinyl-1H-1,2,4-triazole. (55 mg, 36%). m/e⁺=338 (M+H⁺).

Example 2103-((1H-1,2,4-triazol-5-yl)methyl)-6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridine(210)

To a solution of mercuric trifluoroacetate (128 mg, 0.30 mmol) in 0.3 mLof water was added 0.3 mL of THF. The yellow suspension thus formed wasmled to 0° C., and6-fluoro-2-(4-fluorophenyl)-3-((1-vinyl-1H-1,2,4-triazol-5-yl)methyl)imidazo[1,2-a]pyridine(101 mg, 0.30 mmol) was added portion wise. After the addition was over,the reaction mixture was allowed to warm to room temperature and stirredfor 12 h. After cooling to 0° C., 0.3 mL of 3 N NaOH followed by 0.3 mLof 0.5 M NaBH₄ in 3 N NaOH was added to the mixture. The mercury wasallowed to settle, and the supernatant liquid decanted and extractedwith CH2CH2. The extract was dried over anhydrous Na₂SO₄ andconcentrated to give the crude product which was purified silica gelchromatography. 28 mg, 30% yield. m/e⁺=312 (M+H⁺). ¹H-NMR (400 MHz,CD₃OD, δ): 8.41 (m, 1H), 8.33 (s, 1H), 7.79 (m, 2H), 7.60 (m, 1H), 7.33(m, 1H), 7.21 (m, 2H), 4.53 (s, 2H).

Example 2113-((1H-1,2,4-triazol-5-yl)methyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine(211)

The tilte compound was prepared according to the experimentals describedfor compound 210 from2-(4-chlorophenyl)-3-((1-vinyl-1H-1,2,4-triazol-5-yl)methyl)imidazo[1,2-a]pyridine.m/e⁺ 310 for C16H13ClN5 (M+H)⁺.

Example 212 Ethyl3-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate(212) Step 1:2-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetonitrile

30.0 g of molecular sieves were activated under vacuum, at 100° C., for1 h. 5.00 g of 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride (15.94 mmol, 1 eq), 9.38 g of NaCN (191.3 mmol, 12 eq),428 mg of Bu₄NCN (1.59 mmol, 0.1 eq), 9.56 g of NaI (63.77 mmol, 4 eq)and 150 mL of ACN were added. The mixture were stirred at RT, O/N.Sieves were filtered and washed with EtOAc. The filtrate was washedtwice with NaHCO₃, dried on MgSO₄, filtered and concentrated to give4.95 g of crude. It was purified by silica gel chromatography(MeOH/CH₂Cl₂, 0 to 5%) and gave two batches: batch#01 (very pure)=3.90g, batch #O₂ (some impurities) was purified on activated carbon to give0.90 g. Total yield=82%. m/e⁺=268 (M+H⁺).

Step 2:2-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-N′-hydroxyacetimidamide

To a suspension of2-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetonitrile (0.13 mol,34.0 g) in absolute EtOH (300 mL) was added NH₂OH.HCl (0.32 mol, 22.1 g)and K₂CO₃ (0.32 mol, 44.1 g), respectively. The mixture was stirred atr.t. overnight, filtrated, and washed with EtOH for 3 times. TheEtOH-filtrate was concertrated to small volume, and the precipitationwas collected by filtration, to give one partial products. The solid wasdispersed into water, sonicated for 10 mins, filtrated, washed withwater, and dried in vacuo, to give another partial products. Combinedtwo portions products added up to 25.0 g (65.4%). m/e⁺=301 (M+H⁺).

Step 3: ethyl3-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate

To a suspension of2-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-N′-hydroxyacetimidamide(83.3 mmol, 25.0 g) in dry CHCl₃ (600 mL) was cooled to −40° C. in anice/EtOH bath under N₂ atmosphere, Py. (100.0 mmol, 8.1 mL) was added inone portion, and followed by slowly adding ethyl 2-chloro-2-oxoacetate(166.6 mmol, 18.6 mL). After that, the reaction mixture was allowed toslowly rise up to r.t., and kept stirring for 1.0 H, D, then heated to80 C. for another 2 hs. The reaction mixture was cooled to r.t. andfiltered, and the filtrate was evaporated under reduced pressure to givethe brown residue, which was applied to C.C.eluted by petroleum/acetone(4:1, 2:1, 1:1, and 0:1). The acetone portion was concentrated in vacuoto give the solid, which was washed with acetone for 3 times, to obtainthe product, 18.0 g (58.0%), as a white solid. m/e⁺=383 (M+H⁺).

Example 213 Ethyl3-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate(213)

The tilte compound was prepared according to the experimentals describedfor compound 212 from3-(chloromethyl)-2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridinehydrochloride. m/e⁺ 401 for C19H15ClFN4O3 (M+H)⁺.

Example 214 Ethyl3-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate(214)

The tilte compound was prepared according to the experimentals describedfor compound 212 from3-(chloromethyl)-2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridinehydrochloride. m/e⁺ 385 for C19H15F2N4O3 (M+H)⁺.

Example 2153-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carbohydrazide(215)

To a solution of ethyl3-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate(10.5 mmol, 4.0 g) in MeOH (50 mL) was cooled to 0° C., and 99%NH₂NH₂.H₂O (62.8 mmol, 3.2 g) was then added dropwise. In the period ofaddition, lots of white precipitate was generated, kept stirring for 15mins, the white solid was collected by filtration. The white solid wasdispersed into MeOH again, sonicated for 10 mins, filtered, to give thefinal product (3.3 g, 86.0%). m/e⁺=369 (M+H⁺). ¹H NMR (400 MHz, inDMSO-d₆): δ 10.9-10.5 (1H, D, brd, NH), δ 8.44-8.42 (1H, D, d, J=6.8 Hz,ArH), δ 7.87-7.85 (2H, D, dd, J=6.4, 1.6 Hz, ArH), δ 7.67-7.64 (1H, D,d, J=9.2 Hz, ArH), δ 7.56-7.54 (2H, D, dd, J=6.4, 1.6 Hz, ArH), δ7.38-7.25 (1H, D, m, ArH), δ 5.01-4.75 (2H, D, brd, NH₂), δ 4.75 (2H, D,s, CH₂).

Example 2163-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carbohydrazide(216)

The title compound was prepared in the same fashion as that for compound215 from ethyl3-((2-((4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylateand hydrazine hydrate. m/e⁺=387 (M+H⁺). ¹H NMR (400 MHz, in DMSO-d₆): δ10.75 (1H, D, brs, NH), δ 8.70-8.68 (1H, D, dd, J=4.4, 2.0 Hz, ArH), δ7.83-7.80 (2H, D, d, J=8.4 Hz, ArH), δ 7.75-7.71 (1H, D, dd, J=10.0, 5.2Hz, ArH), δ 7.55-7.53 (2H, D, d, J=8.4 Hz, ArH), δ 7.47-7.42 (1H, D, dt,J=8.4, 2.4 Hz, ArH), δ 5.01-4.75 (2H, D, brd, NH₂), δ 4.74 (2H, D, s,CH₂).

Example 2173-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide(217)

The title compound was prepared in the same fashion as that for compound215 from ethyl3-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylateand saturated ammonia in MeOH. (47 mg, 90.0%), as a white solid.m/e⁺=372 (M+H⁺). ¹H NMR (300 MHz, in DMSO-d₆): δ 8.68 (2H, D, brd, NH₂),δ 8.39 (1H, D, s, ArH), δ 7.82-7.80 (2H, D, d, J=8.4 Hz, ArH), δ7.75-7.71 (1H, D, dd, J=9.6, 5.2 Hz, ArH), δ 7.55-7.53 (2H, D, d, J=8.4Hz, ArH), δ 7.47-7.44 (1H, D, m, ArH), and 6 4.74 (2H, D, s, CH₂).

Example 2183-((2-(4-fluorophenyl)-6-chloroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-N-methyl-carboxamide(218)

The title compound was prepared in the same fashion as that for compound215 from ethyl3-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylateand methylamine. m/e⁺=386 (M+H⁺). ¹H NMR (400 MHz, in DMSO-d₆): δ 9.25(H, D, brd, NH), δ 8.69-8.67 (1H, D, d, J=5.2, 2.0 Hz, ArH), δ 7.81-7.79(2H, D, dd, J=9.2, 5.6 Hz, ArH), δ 7.75-7.71 (1H, D, dd, J=9.6, 5.2 Hz,ArH), δ 7.55-7.53 (1H, D, dt, J=9.6, 2.0 Hz, ArH), δ 7.47-7.42 (1H, D,t, J=8.8, ArH), δ 4.75 (2H, D, s, CH₂), and 2.77 (3H, D, s, CH₃).

Example 2193-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-N,N-dimethyl-carboxamide(219)

The title compound was prepared in the same fashion as that for compound215 from ethyl3-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylateand dimethylamine. m/e⁺=400 (M+H⁺). ¹H NMR (400 MHz, in DMSO-d₆): δ8.76-8.74 (1H, D, m, ArH), δ 7.83-7.81 (2H, D, d, J=8.4 Hz, ArH), δ7.75-7.71 (1H, D, m, ArH), δ 7.56-7.54 (2H, D, d, J=8.6 Hz, ArH), δ7.47-7.42 (1H, D, m, ArH), and 6 4.78 (2H, D, s, CH₂), 3.09 (3H, D, s,CH₃), 3.02 (3H, D, s, CH₃).

Example 2203-((2-(4-fluorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-N-methyl-carboxamide(220)

The title compound was prepared in the same fashion as that for compound215 from ethyl3-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylateand saturated ammonia in MeOH. m/e⁺=356 (M+H⁺). ¹H NMR (300 MHz, inDMSO-d₆): δ 8.68 (2H, D, brd, NH₂), δ 8.39 (1H, D, s, ArH), δ 7.84-7.80(2H, D, d, J=8.4 Hz, ArH), δ 7.75-7.71 (1H, D, dd, J=9.6, 5.2 Hz, ArH),δ 7.46-7.41 (1H, D, m, ArH), δ 7.34-7.30 (2H, D, m, ArH), and 6 4.73(2H, D, s, CH₂).

Example 2213-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N-methyl-1,2,4-oxadiazole-5-carboxamide(221)

The title compound was prepared in the same fashion as that for compound215 from ethyl3-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylateand methylamine. m/e⁺=370 (M+H⁺). ¹H NMR (400 MHz, in DMSO-d₆): δ 9.23(H, D, brd, NH), δ 8.66-8.65 (1H, D, dd, J=5.2, 2.0 Hz, ArH), δ7.81-7.78 (2H, D, m, ArH), δ 7.45-7.40 (1H, D, dd, J=9.6, 5.2 Hz, ArH),δ 7.32-7.28 (2H, D, m, ArH), δ 4.72 (2H, D, s, CH₂), and 2.76 (3H, D, s,CH₃).

Example 2223-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-N-hydroxy-1,2,4-oxadiazole-5-carboxamide(222)

To a solution of ethyl3-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate(0.125 mmol, 50.0 mg) in EtOH (10 mL) was added NH₂OH.HCl (0.75 mmol,52.1 mg) and K₂CO₃ (0.375 mmol, 51.8 mg) at r.t. The reaction mixturewas stirred for 30 mins at r.t., and filtered. The filtrate wasconcentrated under reduced pressure, to give the title product (30 mg,60.0%), as a white solid. m/e⁺=388 (M+H⁺). ¹H NMR (300 MHz, in DMSO-d₆):δ 12.14 (1H, D, brd, OH), δ 9.87 (1H, D, brd, NH), δ 8.69-8.68 (1H, D,dd, J=5.2, 2.4 Hz, ArH), δ 7.81-7.79 (2H, D, d, J=8.4 Hz, ArH), δ7.74-7.71 (1H, D, dd, J=9.6, 5.2 Hz, ArH), δ 7.55-7.53 (2H, D, d, J=8.4Hz, ArH), δ 7.47-7.41 (1H, D, m, ArH), and 6 4.73 (2H, D, s, CH₂).

Example 2233-((2-(4-fluorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-N-hydroxy-1,2,4-oxadiazole-5-carboxamide(223)

The title compound was prepared in the same fashion as that for compound222 from ethyl ethyl3-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylateand hydroxylamine hydrochloride. m/e⁺=372 (M+H⁺). ¹H NMR (400 MHz, inDMSO-d₆): δ 8.68-8.67 (1H, D, dd, J=5.2, 2.0 Hz, ArH), δ 7.84-7.79 (2H,D, dd, J=9.2, 5.6 Hz, ArH), δ 7.73-7.70 (1H, D, dd, J=9.6, 5.2 Hz, ArH),δ 7.45-7.40 (1H, D, dt, J=9.6, 2.0 Hz, ArH), δ 7.34-7.29 (1H, D, t,J=8.8, ArH), and 6 4.70 (2H, D, s, CH₂).

Example 2243-((2-(4-fluorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-N-methyoxy-1,2,4-oxadiazole-5-carboxamide(224)

The title compound was prepared in the same fashion as that for compound222 from ethyl ethyl3-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylateand O-methylhydroxylamine hydrochloride. m/e⁺=386 (M+H⁺). ¹H NMR (400MHz, in DMSO-d₆): δ 8.55-8.53 (1H, m, ArH), δ 7.88-7.84 (2H, D, dd,J=9.2, 5.6 Hz, ArH), δ 7.67-7.63 (1H, D, dd, J=9.6, 5.2 Hz, ArH), δ7.43-7.38 (2H, D, m ArH), δ 7.30-7.25 (1H, D, m, ArH), and 6 4.59 (2H,D, s, CH₂). 6 3.77 (3H, D, s, CH₃).

Example 2253-((6-fluoro-2-(4-fluorophenyl)imidazo-[1,2-a]pyridin-3-yl)methyl)-N-hydroxy-N-methyl-1,2,4-oxadiazole-5-carboxamide(225)

The title compound was prepared in the same fashion as that for compound222 from ethyl ethyl3-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylateand N-methylhydroxylamine hydrochloride. m/e⁺=386 (M+H⁺). ¹H NMR (400MHz, in DMSO-d₆): δ 10.97 (1H, s, OH), δ 8.84 (1H, m, ArH), δ 7.85-7.78(3H, m, ArH), δ 7.58-7.39 (1H, m, ArH), δ 7.39-7.34 (2H, D, m ArH), δ7.30-7.25 (1H, D, m, ArH), and 6 4.80 (2H, D, s, CH₂). 6 3.28 (3H, D, s,CH₃).

Example 226N-hydroxy-3-((2-phenylimidazo[1,2-a]pyridin-3-yl)-methyl)-1,2,4-oxadiazole-5-carboxamide(226)

The title compound was prepared in the same fashion as that for compound222 from ethyl3-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylateand hydroxylamine hydrochloride. m/e⁺=370 (M+H⁺). ¹H NMR (400 MHz, inDMSO-d₆): δ 8.43-8.41 (1H, D, d, J=7.2 Hz, ArH), δ 8.31 (1H, D, s, ArH),δ 7.88-7.86 (2H, D, d, J=8.4 Hz, ArH), δ 7.65-7.62 (1H, D, d, J=9.2 Hz,ArH), δ 7.57-7.54 (1H, D, d, J=8.4 Hz, ArH), δ 7.35-7.31 (1H, D, t,J=8.0, ArH), δ 7.04-7.00 (1H, D, t, J=8.0, ArH), and δ 4.62 (2H, D, s,CH₂).

Example 2273-((2H-1,2,3-triazol-4-yl)methyl)-6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine(227)

Step 1: To a suspension of6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride (1.7-2.9 mmol, 1.0 eq) in THF (20-40 mL) at −40° C. wasadded propynyl magnesium bromide (1.7-2.9 mmol, 1.0 eq) dropwise. After10 min, more Grignard reagent (1.7-2.9 mmol, 1.0 eq) was added dropwiseand the reaction was warmed to −20° C. for 30 min, followed by additionof more Grignard reagent (0.85-1.4 mmol, 0.5 eq). After this time thereaction mixture was warmed to 0° C. for 2H, D and then quenched with 1MHCl (10 mL). The reaction mixture was neutralized with satd. aq. NaHCO₃and extracted with ethyl acetate (50 mL). The organic layer was washedwith brine, dried, concentrated, and purified by chromatography (silicagel, heptanes/ethyl acetate gradient) to afford.6-chloro-2-(4-chlorophenyl)-3-(prop-2-ynyl)imidazo[1,2-a]pyridine. (0.66g, 73% yield). M/e⁺ 301.1 for C₁₆H₁₀Cl₂N₂ (M+H)⁺; ¹H-NMR (500 MHz,CDCl₃, δ) 8.19 (d, J=1.5 Hz, 1H), 7.71-7.69 (m, 2H), 7.61 (d, J=9.5 Hz,1H), 7.48-7.46 (m, 2H), 7.22 (dd, J=2.0, 9.5 Hz, 1H), 3.93 (d, J=3.0 Hz,2H), 2.19 (t, J=3.0 Hz, 1H).

Step 2: A mixture of6-chloro-2-(4-chlorophenyl)-3-(prop-2-ynyl)imidazo[1,2-a]pyridine alkyne(0.8 mmol, 1.0 eq) and trimethylsilylazide (20 eq) was stirred in amicrowave (300 W, 170° C.) for 5 hours. After this time the reactionmixture was diluted with CH₂Cl₂ (25 mL) and 1M NaOH (5 mL) and stirredat room temperature for 18 hours. The reaction mixture was concentratedand used without further purification or characterization. An aliquot ofthe crude products was purified by reverse phase preparatory HPLC(silica gel, acetonitrile/water gradient) to obtain the desired product.M/e⁺ 344.1 for C₁₆H₁₁Cl₂N₅ (M+H)⁺; ¹H-NMR (300 MHz, DMSO-d₆, δ) 14.83(s, 1H), 8.67 (d, J=1.2 Hz, 1H), 7.89-7.86 (m, 3H), 7.70-7.66 (m, 1H),7.56-7.53 (m, 2H), 7.35 (dd, J=9.5, 2.0 Hz, 1H), 4.57 (s, 2H).

Example 2286-chloro-2-(4-chlorophenyl)-3-((5-methyl-2H-1,2,3-triazol-4-yl)methyl)imidazo[1,2-a]pyridine(228)

The title compound was prepared according to the experimental describedfor compound 227 from6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridinehydrochloride and prop-1-ynylmagnesium bromide. m/e⁺ 359 for C17H14Cl2N5(M+H)⁺.

Example 2296-Chloro-2-(4-chlorophenyl)-3-((2,5-dimethyl-2H-1,2,3-triazol-4-yl)methyl)imidazo[1,2-a]pyridine(229)

To a suspension of the6-chloro-2-(4-chlorophenyl)-3-((5-methyl-2H-1,2,3-triazol-4-yl)methyl)imidazo[1,2-a]pyridine(0.6-1.7 mmol, 1.0 eq) in DMF or THF (5-20 mL) was added potassiumcarbonate (3-5 eq) and either methyliodide or ethyliodide (3-5 eq) andthe reaction mixture was heated at 75-85° C. for 18 h. After this timethe reaction mixture was cooled and diluted with water (20-50 mL) andethyl acetate (20-50 mL) and the layers were separated. The aqueouslayer was extracted with ethyl acetate (10-30 mL) and the combinedorganic layers were dried over Na₂SO₄, concentrated and the residue waspurified by chromatography (silica gel, heptane/ethyl acetate gradient)or reverse phase preparatory HPLC (acetonitrile/water gradient) toobtain the desired product. (0.14 g, 26% yield). M/e⁺ 372.1 forC₁₈H₁₅Cl₂N₅ (M+H)⁺; ¹H-NMR (500 MHz, CDCl₃, δ) 8.09 (d, J=2.0 Hz, 1H),7.69-7.67 (m, 2H), 7.58 (d, J=9.5 Hz, 1H), 7.45-7.44 (m, 2H), 7.17 (dd,J=9.5, 2.0 Hz, 1H), 4.33 (s, 2H), 4.05 (s, 3H), 2.01 (s, 3H).

Example 2302-(4-chlorophenyl)-3-((5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)methyl)imidazo[1,2-a]pyridine(230)

Step 1: A mixture of ethyl2-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetate (prepared from2-(4-chlorophenyl)imidazo[1,2-a]pyridine and ethyl 2-oxoacetate byreluxing in toluene with catalytic amount of pTSA followed bydehydroxylation with P2I4 as illustrated in WO 2005/044818) (100 mg) wastreated with hydrazine hydrate (0.5 ml) until the reacyion was complete.Excess hydrazine was removed under reduced pressure. The residue wasdissolved in CH₂Cl₂ (10 mL) and was washed with sat. NaHCO₃, brine,dried with Na₂SO₄ and concentrated. m/e⁺ 301 for C₁₅H₁₄N₄₀ (M+H)⁺.

Step 2: A mixture of2-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetohydrazide (0.55mmol, 1.0 eq) in DMF (1-2 ml) and picolinimidamide hydrochloride (1.5eq) was heated at 120° C. for 3 h. The mixture was cooled to rt, treatedwith sat. NaHCO₃ (5 ml), extracted with CH₂Cl₂ (10 ml). The organicsolution was dried with Na₂SO₄, evaporated under vacuum. The crudeproduct was purified by HPLC. M/e⁺ 387 for C₂₁H₁₆ClN₆ (M+H)⁺; ¹H-NMR(400 MHz, CD₃OD) δ 9.11 (d, J=1.4 Hz, 1H), 8.56 (d, J=3.7 Hz, 1H), 8.36(d, J=6.2 Hz, 2H), 7.77 (d, J=8.4 Hz, 2H), 7.70 (dt, J=8.4, 2.9 Hz, 2H),7.36 (m, 2H), 6.99 (m, 2H), 4.64 (s, 2H) ppm.

Example 2312-(4-chlorophenyl)-3-((5-isopropyl-4H-1,2,4-triazol-3-yl)methyl)imidazo[1,2-a]pyridine(231)

The title compound was prepared according to the experimental describedfor compound 230 from2-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetohydrazide andisobutyrimidamide hydrochloride. M/e⁺ 352 for C₁₉H₁₉ClN₅ (M+H)⁺; ¹H-NMR(400 MHz, CDCl₃) δ 8.05 (m, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.27 (m, 4H),7.04 (t, J=7.3 Hz, 1H), 6.75 (t, J=6.6 Hz, 1H), 4.42 (s, 2H), 3.12 (m,1H), 1.39 (s, 3H), 1.37 (s, 3H) ppm.

Example 2326-chloro-3-((5-isopropyl-4H-1,2,4-triazol-3-yl)methyl)-2-phenylimidazo[1,2-a]pyridine(232)

The title compound was prepared according to the experimental describedfor compound 230 from2-(6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)acetohydrazide andisobutyrimidamide hydrochloride. M/e⁺ 352 for C₁₉H₁₉ClN₅ (M+H)⁺; ¹H-NMR(400 MHz, CDCl₃) δ 8.23 (s, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.29 (m, 5H),7.00 (dd, J=9.5, 1.8 Hz, 1H), 4.40 (s, 2H), 3.03 (m, 1H), 1.29 (s, 3H),1.28 (s, 3H) ppm.

Example 2332-(4-chlorophenyl)-3-((5-methyl-4H-1,2,4-triazol-3-yl)methyl)imidazo[1,2-a]pyridine(233)

The title compound was prepared according to the experimental describedfor compound 230 from2-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetohydrazide andacetimidamide hydrochloride. M/e⁺ 324 for C₁₇H₁₅ClN₅ (M+H)⁺; ¹H-NMR (400MHz, CD₃OD) δ 8.27 (d, J=6.6 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.58 (d,J=9.1 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.35 (t, J=6.9 Hz, 1H), 6.95 (t,J=6.2 Hz, 1H), 4.46 (s, 2H), 2.37 (s, 3H) ppm.

Example 2346-chloro-3-((5-methyl-4H-1,2,4-triazol-3-yl)methyl)-2-phenylimidazo[1,2-a]pyridine(234)

The title compound was prepared according to the experimental describedfor compound 230 from2-(6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)acetohydrazide andacetimidamide hydrochloride. M/e⁺ 324 for C₁₇H₁₅ClN₅ (M+H)⁺; ¹H-NMR (400MHz, CD₃OD) δ 8.43 (s, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.63 (m, 1H), 7.57(d, J=9.9 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.39 (m, 2H), 4.46 (s, 2H),2.38 (s, 3H) ppm.

Example 2355-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N-methyl-1,3,4-thiadiazol-2-amine(235)

A solution of2-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetohydrazide (0.1 g,0.33 mmol) in EtOH (1 mL) was treated with isothiocyanatomethane (0.023mL, 0.33 mmol) and refluxed for 3 h. The precipitated thiosemicarbazidewas filtered and dissolved in concentrated sulfuric acid. The reactionmixture was stirred for 30 min at rt. The mixture was poured into coldwater and the precipitated product was filtered in vacuo and washed withditilled water. The crude product was recrystallized in EtOH to providethe title product as a yellow solid. M/e⁺ 356 for C₁₇H₁₅ClN₅S (M+H)⁺;¹H-NMR (400 MHz, CDCl₃) δ 8.15 (d, J=6.9 Hz, 1H), 7.71 (d, J=8.4 Hz,2H), 7.63 (d, J=9.1 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.22 (m, 2H), 6.84(t, J=6.6 Hz, 1H), 4.65 (s, 2H), 2.98 (s, 3H) ppm.

Example 2363-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one(236)

A solution of2-(6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)-N′-hydroxyacetimidamide(0.040 g, 0.13 mmol) and triethylamine (0.025 mL, 0.198 mmol) in CHCl₃(1 mL) was treated with phenyl carbonochloridate (0.018 mL, 0.19 mmol)and stirred for 1 h. The reaction mixture was washed with water (30 mL)and dichloromethane (30 mL). The organic solution was dried with Na₂SO₄,evaporated under vacuum. The crude product was purified by HPLC toprovide the title product. M/e⁺ 329 for C₁₆H₁₁F₂N₄O₂ (M+H)⁺; ¹H-NMR (400MHz, CDCl₃) δ 8.69 (dd, J=4.0, 2.2 Hz, 1H), 7.77 (dd, J=9.9, 4.7 Hz,1H), 7.69 (m, 2H), 7.62 (m, 2H), 7.29 (m, 2H), 4.45 (s, 2H) ppm.

Example 2371-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-(2-(dimethylamino)ethylamino)-1H-pyrrol-2(5H)-one (237)

Step 1: A mixture of(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methanamine (850 mg, 3.31mmol), 380 uL of (Z)-methyl 4-chloro-3-methoxybut-2-enoate (3.31 mmol, 1eq), 1.37 g of potassium carbonate (9.94 mmol, 3 eq), and 50 mg ofsodium iodide (0.331 mmol, 0.1 eq) in 15 mL of CAN was heated to 60° C.and refluxed for 2 h. LCMS showed a mixture of the product, and the nextstep product (cyclization). Let the reaction go until no more Z-methyl4-chloro-3-methoxybut-2-enoate was detedted. After cooled to roomtemperaturem, the mixture was filtere to remove the solid. The filtratewas concentrated under vacuum. The crude was used in next step withoutfurther purification. (1.07 g, 84%). m/e⁺=386 (M+H⁺).

Step 2: A mixture of 1.19 g of (Z)-methyl4-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methylamino)-3-methoxybut-2-enoate(2.75 mmol, 1 eq) in 12 mL acetic acid (excess) was stirred at 90° C.and refluxed for 2H, D, then diluted with EtOAc, washed with an excessof NaHCO₃ (aq, sat), dried on MgSO₄, filtered and concentrated to give788 mg of a yellow solid. The product was then purified by a silica gelchromatography (EtOAc/Hexane, 2 to 100%) (420 mg, 43%). m/e⁺=354 (M+H⁺).

Step 3: To a mixture of 100 mg of1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-methoxy-1H-pyrrol-2(5H)-one(0.251 mmol, 1 eq) in 1 mL of N,N-dimethylethane-1,2-diamine in a sealedtube, one drop of HCl was added. The solution was heated at 140° C.,0/N. The mixture was then diluted with EtOAc, washed with an excess ofNaHCO₃ (aq, sat), dried on MgSO₄, filtered and concentrated. The crudewas purified on silica gel chromatography (MeOH:NH₄OH (95:5)/EtOAc, 0 to15%). The product was then washed with ether to give a white solid. (37mg, 32%) m/e⁺=410 (M+H⁺). ¹H-NMR (400 MHz, CDCl₃, δ): 8.51 (d, 1H, D,J=6.6 Hz), 7.72 (d, 2H, D, J=8.6 Hz), 7.61 (d, 1H, D, J=9.2 Hz), 7.45(d, 2H, D, J=8.4 Hz), 7.24 (t, 1H, D, J=8.8 Hz), 6.85 (t, 1H, D, J=6.4Hz), 5.06 (s, 2H), 4.89 (m, 1H), 4.67 (s, 1H), 3.56 (s, 2H), 2.99 (m,2H), 2.42 (m, 2H), 2.15 (s, 6H).

Example 2381-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-(4-methylpiperazin-1-yl)-1H-pyrrol-2(5H)-one(238)

The title compound was prepared according to the experimental forcompound 237 from1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-methoxy-1H-pyrrol-2(5H)-oneand 1-methylpiperazine. (56 mg, 47%) m/e⁺=422 (M+H⁺). ¹H-NMR (400 MHz,CDCl₃, δ): 8.47 (d, 1H, D, J=7.0 Hz), 7.73 (d, 2H, D, J=8.4 Hz), 7.62(d, 1H, D, J=9.1 Hz), 7.47 (d, 2H, D, J=8.4 Hz), 7.25 (t, 1H, D, J=7.3Hz), 6.85 (t, 1H, D, J=6.4 Hz), 5.09 (s, 2H), 4.74 (s, 1H), 3.57 (s,2H), 3.03 (m, 4H), 2.36 (m, 4H), 2.27 (s, 3H).

Example 2391-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-(piperidin-1-yl)-1H-pyrrol-2(5H)-one(239)

The title compound was prepared according to the experimental forcompound 237 from1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-methoxy-1H-pyrrol-2(5H)-oneand piperidine. (62 mg, 54%) m/e⁺=407 (M+H⁺). ¹H-NMR (400 MHz, CDCl₃,δ): 8.49 (d, 1H, D, J=7.0 Hz), 7.73 (d, 2H, D, J=8.4 Hz), 7.62 (d, 1H,D, J=9.2 Hz), 7.47 (d, 2H, D, J=8.4 Hz), 7.25 (t, 1H, D, J=7.3 Hz), 6.85(t, 1H, D, J=7.3 Hz), 5.09 (s, 2H), 4.69 (s, 1H), 3.56 (s, 2H), 2.99 (m,4H), 1.63 (m, 2H), 1.53 (m, 4H).

Example 2401-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-(3-hydroxypyrrolidin-1-yl)-1H-pyrrol-2(5H)-one(240)

The title compound was prepared according to the experimental forcompound 237 from1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-methoxy-1H-pyrrol-2(5H)-oneand pyrrolidin-3-ol. (33 mg, 32%) m/e⁺=409 (M+H⁺). ¹H-NMR (400 MHz,CDCl₃, δ): 8.46 (d, 1H, D, J=7.0 Hz), 7.73 (d, 2H, D, J=8.4 Hz), 7.61(d, 1H, D, J=9.1 Hz), 7.46 (d, 2H, D, J=8.4 Hz), 7.25 (t, 1H, D, J=7.3Hz), 6.84 (t, 1H, D, J=7.3 Hz), 5.09 (s, 2H), 4.57 (s, 1H), 4.53 (m,1H), 3.55 (s, 2H), 3.2 (m, 4H), 2.1 (m, 3H).

Example 2411-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-(4-hydroxypiperidin-1-yl)-1H-pyrrol-2(5H)-one(241)

The title compound was prepared according to the experimental forcompound 237 from1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-methoxy-1H-pyrrol-2(5H)-oneand piperidin-4-ol. (49 mg, 41%) m/e⁺=423 (M+H⁺). ¹H-NMR (400 MHz,CDCl₃, δ): 8.47 (d, 1H, D, J=7.0 Hz), 7.73 (d, 2H, D, J=8.4 Hz), 7.62(d, 1H, D, J=9.2 Hz), 7.47 (d, 2H, D, J=8.8 Hz), 7.25 (t, 1H, D, J=7.3Hz), 6.85 (t, 1H, D, J=7.3 Hz), 5.09 (s, 2H), 4.73 (s, 1H), 3.87 (m,1H), 3.57 (s, 2H), 3.25 (m, 2H), 2.87 (m, 2H), 1.7 (m, 4H).

Example 242 Preparation of1-((2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-(2-(dimethylamino)ethylamino)-1H-pyrrol-2(5H)-one(242)

The title compound was prepared according to the experimental forcompound 237 from(2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl)methanamine. m/e⁺=454(M+H⁺). ¹H-NMR (400 MHz, CDCl₃, δ): 8.51 (d, 1H, D, J=5.8 Hz), 7.63 (m,5H), 7.26 (m, 1H), 6.85 (t, 1H, D, J=6.6 Hz), 5.06 (s, 2H), 4.88 (m,1H), 4.67 (s, 1H), 3.55 (s, 1H), 2.99 (m, 2H), 2.42 (m, 2H), 2.16 (s,6H).

Example 243N¹-(6-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-4-yl)-N²,N²-dimethylethane-1,2-diamine(243) Step 1:6-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-4-ol

To 20 mL of ACN were added 500 mg of2-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetonitrile (1.87 mmol,1 eq), 1.12 g of 4,6-dichloropyrimidine (7.47 mmol, 4 eq) and 840 mg ofKOBu (7.47 mmol, 4 eq). The mixture was stirred at RT, 0/N. The solutionwas then diluted with EtOAc, washed with NaHCO₃, dried on MgSO₄,filtered and concentrated to give 1.32 g of a crude nitrile intermediate(m/e⁺=380). This intermediate was dissolved in a mixture of 36 mL of TFAand 360 uL of water. It was heated to 150° C. under microwaves for 5min. Excess TFA was then removed by blowing a steam of N₂ over thesolution. The residue was diluted with EtOAc, washed with NaHCO₃, driedon MgSO₄, filtered and concentrated to give 840 mg of the final crude.It was purified by silica gel chromatography (MeOH/CH₂Cl₂, 1 to 5%) (360mg, 57%). m/e⁺=337 (M+H⁺).

Step 2:2-(4-chlorophenyl)-3-((6-chloropyrimidin-4-yl)methyl)imidazo[1,2-a]pyridine

To a mixture of 360 mg of642-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-4-ol(1.07 mmol, 1 eq) in 5 mL of ACN was added 0.98 mL of POCl₃ (10.7 mmol.10 eq). The mixture was heated to 65° C. and stirred for 1 h. Thesolution was then diluted with EtOAc, washed with NaHCO₃, dried onMgSO₄, filtered and concentrated (210 mg, 55%) m/e⁺=355 (M+H⁺).

Step 3:N1-(6-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-4-yl)N2,N2-dimethylethane-1,2-diamine

A mixture of 100 mg of2-(4-chlorophenyl)-3-((6-chloropyrimidin-4-yl)methyl)imidazo[1,2-a]pyridine(0.282 mmol, 1 eq) in 1 mL of N,N-dimethylethane-1,2-diamine (excess) ina sealed tube was heated to 95° C. for 2 h. The solution was thendiluted with EtOAc, washed with water, dried on MgSO₄, filtered andconcentrated. The crude was purified by silica gel chromatography(MeOH:NH₄OH (95:5)/EtOAc, 0 to 15%). The product was finally washed withether (33 mg, 29%) m/e⁺=407 (M+H⁺). ¹H-NMR (400 MHz, CDCl₃, δ): 8.55 (s,1H), 7.90 (d, 1H, D, J=6.6 Hz), 7.73 (d, 2H, D, J=8.4 Hz), 7.67 (d, 1H,D, J=9.2 Hz), 7.42 (d, 2H, D, J=8.8 Hz), 7.25 (t, 1H, D, J=7.7 Hz), 6.81(t, 1H, D, 7.7 Hz), 5.86 (s, 1H), 4.38 (s, 2H), 2.43 (m, 2H), 2.17 (s,6H).

Example 2442-(4-chlorophenyl)-3-((6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)imidazo[1,2-a]pyridine(244)

The title compound was prepared according to Method D and theexperimental for compound 243 from2-(4-chlorophenyl)-3-((6-chloropyrimidin-4-yl)methyl)imidazo[1,2-a]pyridineand 1-methylpiperazine. (59 mg, 45%) m/e⁺=419 (M+H⁺). ¹H-NMR (400 MHz,CDCl₃, δ): 8.57 (s, 1H), 7.93 (d, 1H, D, J=7.0 Hz), 7.73 (d, 2H, D,J=8.4 Hz), 7.67 (d, 1H, D, J=8.8 Hz), 7.42 (d, 2H, D, J=8.8 Hz), 7.25(t, 1H, D, J=7.7 Hz), 6.81 (t, 1H, D, 7.7 Hz), 6.05 (s, 1H), 4.39 (s,2H), 3.48 (m, 4H), 2.37 (m, 4H), 2.28 (s, 3H).

As previously stated, the Examples included herein are for illustrativepurposes only, and the invention is in no way limited to the embodimentsprepared in the Examples.

Example 245

Compounds of the invention were assessed for their binding to thebenzodiazepine receptor by the test of Speth et al. [Life Sci. 24, 351(1979)] for central benzodiazepine receptors and LeFur et al. [Life Sci.33, 449 (1983)] for peripheral receptors. The compounds were testedfirst at 1.0E-09, 1.0E-07 and 1.0E-05 M in single determination. In theassays where a compound showed a % inhibition higher than 50% at eitherconcentration, it was tested further at five concentrations in duplicateto obtain competition curves. The specific ligand binding to thereceptor is defined as the difference between the total binding and thenonspecific binding determined in the presence of an excess ofunlabelled ligand. In each experiment, the respective reference compoundwas tested concurrently with the test compounds in order to assess theassay suitability. It was tested at several concentrations (for IC₅₀value determination), and the data were compared with historical values.The assay was rendered valid if suitability criteria were met.

BZD central binding data for the compounds is provided in Table 3,wherein is provided the percent inhibition of central BZD in thepresence of 1000 nM of the compound. The sign “++” indicates thatpercentage of inhibition of central BZD site binding is greater than 80%in the presence of 1000 nM of the compound; the sign “+” indicates thatpercentage of inhibition of central BZD site binding is greater than 50%but less than 80% in the presence of 1000 nM of the compound; the sign“−” indicates that percentage of inhibition of central BZD site bindingis less than 50% in the presence of 1000 nM of the compound.

TABLE 3 Compound Index % Inhibition at 1000 nM for CBZD 1 ++ 2 ++ 3 + 4++ 5 ++ 6 ++ 7 ++ 8 ++ 9 ++ 10 ++ 11 ++ 12 ++ 13 + 14 − 15 ++ 16 ++ 17++ 18 ++ 19 ++ 21 ++ 22 ++ 23 ++ 24 ++ 26 ++ 27 ++ 28 ++ 29 ++ 30 + 31 +32 ++ 33 ++ 34 + 35 + 36 + 37 − 38 ++ 39 ++ 40 ++ 41 ++ 43 ++ 44 ++ 45 +46 ++ 47 + 48 ++ 49 ++ 50 + 51 ++ 54 ++ 55 ++ 56 ++ 57 ++ 58 ++ 59 + 60++ 61 ++ 62 ++ 63 ++ 64 ++ 65 ++ 67 ++ 68 ++ 69 ++ 70 + 71 + 72 ++ 74 ++75 ++ 76 ++ 77 ++ 78 ++ 79 + 80 ++ 81 ++ 82 ++ 87 + 88 ++ 89 ++ 90 ++ 91++ 92 ++ 93 ++ 94 ++ 95 ++ 96 ++ 97 ++ 101 ++ 102 + 104 ++ 107 ++ 108 ++109 ++ 111 ++ 112 ++ 113 ++ 115 ++ 116 ++ 117 ++ 118 ++ 119 ++ 120 ++121 ++ 122 ++ 123 ++ 124 ++ 125 ++ 126 − 127 + 128 ++ 129 ++ 130 ++ 131++ 132 ++ 133 ++ 134 ++ 135 ++ 136 ++ 137 ++ 138 ++ 139 ++ 140 ++ 143 ++144 ++ 146 ++ 147 ++ 148 ++ 149 ++ 150 ++ 151 ++ 152 + 153 ++ 154 ++155 + 156 ++ 157 ++ 158 ++ 159 ++ 160 ++ 161 ++ 162 ++ 163 ++ 164 ++ 165++ 166 ++ 167 ++ 168 ++ 169 ++ 170 ++ 171 ++ 172 ++ 173 ++ 174 ++ 175 ++176 ++ 177 + 178 + 179 ++ 180 ++ 181 ++ 183 ++ 184 ++ 185 ++ 186 ++ 187++ 188 ++ 189 ++ 190 ++ 191 ++ 192 ++ 193 ++ 194 + 195 ++ 196 ++ 198 ++199 ++ 200 ++ 201 ++ 202 ++ 203 ++ 204 ++ 205 ++ 206 ++ 207 ++ 210 ++227 ++ 229 ++ 230 ++ 231 ++ 232 ++ 233 ++ 234 ++ 235 + 236 ++ 237 ++ 238++ 239 ++ 240 ++ 241 ++ 242 ++ 243 ++ 244 ++

The results of these in vitro tests are accepted by persons of skill inthe art as predictive of therapeutic utility in vivo.

Example 246

Electrophysiology Protocol:

Oocytes were prepared from adult female Xenopus laevis frogs. cRNAencoding human α1, α2, α3, α5, β3 and γ2L GABA_(A) receptor subunits wasinjected into the cytoplasm of stage 5 or 6 oocytes using the RobocyteRobot (Multi Channel Systems, Reutlingen, Germany). Two-electrodevoltage clamp recordings were made in 96-well plates using the RobocyteRobot. Oocytes were impaled using recording heads with two glasselectrodes containing 1.5M potassium acetate and 0.5M KCl and held at amembrane potential of −80 mV. Oocytes were continually perfused with aND96 solution (96 mM NaCl, 2 mM KCl, 0.1 mM CaCl₂, and 5 mM HEPES, pH7.5) using a Gilson 222 XL Liquid Handler and Gilson Minipuls 3Peristaltic Pump (Gilson Medical Electronics, Middleton, Wis., USA). Theprotocol consisted of three 20-s applications of GABA that gave a 20% ofthe maximum response (EC₂₀: 60 μM) to allow for headroom to determine abaseline GABA response. To assess the potentiation, oocytes were firstexposed to a single 1 μM chlordiazepoxide (CDP) as a potentiationstandard. Oocytes with insufficient expression levels (currents belowthreshold) or insufficient γ2L subunit incorporation (judged by rapiddesensitization upon GABA application, or by insufficient potentiationby CDP) were not included in analysis. Following this controlapplication, a given oocyte was exposed to test compounds at 100 nMconcentrations. Only one concentration of one compound was tested peroocyte. Results are displayed in Table 4. The sign “++” indicates thatpercentage of potentiation is greater than or equal to 50% in thepresence of 100 nM of the compound; the sign “+” indicates thatpercentage of potentiation is greater than or equal to 10% but less than50% in the presence of 100 nM of the compound; the sign “0” indicatesthat percentage of potentiation is between about 10% to about −10%; thesign “−” indicates that percentage of potentiation is less than or equalto −10% in the presence of 100 nM of the compound. One skilled in theart will recognize that subtypes contribute to the effects of GABA-Amodulators. Such that compounds favoring different subtypes can havedifferent therapeutic effects. The magnitude of modulation, for example,partial modulators can influence the effects in vivo. “++” indicates agreater modulation that “+” so that at any given subtype “++” inducatesa greater amount of modulation for that subtype. In some embodiments,modulation favoring alpha 1 relative to alpha2 and/or alpha 3 can havesedative hypnotic effects. In other embodiments, compounds with reducedselectivity of alpha 1 can express anxiolytic effects with lesssedation. Compounds with selectivity for alpha 5 can havememory/cognition enhancing effects.

TABLE 4 Percentage of potentiations of compounds for α1, α2, α3 and α5subtype containing GABA-A receptors Compound Index alpha1 alpha2 alpha3alpha5 2 + + 4 + 0 6 + + 7 + + 8 ++ + 9 + + 15 + + + 0 17 + + 0 0 19 + +21 + + + 0 23 + + + 0 25 + ++ 27 + + 29 ++ ++ 32 + + 39 + + + 0 40 0 +42 + + 43 0 + 44 0 0 46 + 0 47 0 0 49 0 + 56 + ++ 57 + ++ 58 + + 0 0 590 0 60 0 + 61 + + ++ 62 + 0 63 + 0 64 + + 72 + ++ + 0 73 + + 76 0 + 770 + 78 + + 81 + + 88 0 + 90 + + 105 + + 106 + + 114 ++ + + 0 115 + +118 + ++ 119 0 + 0 0 120 ++ ++ 121 ++ ++ 123 + + 125 0 + 127 0 + 128 0 +0 + 133 + ++ 0 0 135 ++ 136 + ++ 137 + + 138 + + 139 + + 0 0 145 ++ +147 ++ 150 0 + 157 + 158 0 + + 0 159 + + 160 + + 162 + 165 + + 170 + + +0 179 0 0 183 ++ ++ 0 184 + + 187 − 0 188 ++ ++ 189 ++ ++ 191 + +192 + + 193 + + 195 ++ ++ 196 ++ ++ 198 ++ ++ 200 + ++ 204 0 + 205 0 0 00 206 ++ ++ 207 + + 211 + ++ 215 0 + 216 + ++ + 0 217 + ++ 218 + ++ 2200 + 0 0 221 0 + 222 0 ++ 223 − + 224 0 + 225 − + 227 ++ 229 + +230 + + + + 233 + ++ 234 + ++ 237 0 + 238 + + 240 ++ + 0 0 242 + + 0243 + +

Example 247

Stress-Induced Hyperthermia (SiH) Protocol:

The stress-induced hyperthermia (SiH) test is based on the principlethat animal's have a natural hyperthermic response to stress. The testinvolves taking two measures of rectal temperature in the same animalwithin a 10 minute interval. The two sequential rectal temperaturemeasurements reveal the animal's basal temperature (T1) and 10 minuteslater, an enhanced body temperature (T2) due to the stress of the firstrectal temperature. The difference T2-T1 (delta T) is the SIH response.When anxiolytic drugs are administered prior to recording temperature,they reduce the stress response.

Adult male 129SVEV mice (6 weeks old) from Taconic Laboratories(Germantown, N.Y.) were used in these studies. Upon receipt, mice wereassigned unique identification numbers (tail marked) and were grouphoused in OptiMICE ventilated racks. All animals remained group housedduring the remainder of the study unless indicated otherwise. All micewere acclimated to the colony room for at least two weeks prior totesting and were subsequently tested at 8 weeks of age. During theperiod of acclimation, mice were examined on a regular basis, handled,and weighed to assure adequate healtH, D and suitability. Mice weremaintained on a 12/12 light/dark cycle with the light on at 7:00 a.m.The room temperature was maintained between 20 and 23° C. with arelative humidity maintained between 30% and 70%. Chow and water wereprovided ad libitum for the duration of the study. Animals were notdisturbed between test days.

On the day prior to testing, the mice were brought to the experimentalroom one hour before scheduled lights out and singly housed overnightwith food and water ad libitum. On the morning of the experiment, micewere orally dosed via gavage with vehicle, CDP (10 mg/kg) or compoundsof the present invention (3, 10 or 30 mg/kg) and placed back in thecages. One hour after oral gavage, each animal was removed from theholding cage and held in a supine position and rectal temperature wasmeasured. The rectal probe was attached to a PhysiTemp digitalthermometer (Fisher Scientific) which provides temperature readings at0.1° C. accuracy. The probe remained inside the animal for approximately5 seconds or until body temperature reached stability. This temperaturewas recorded as the baseline rectal temperature (T1). The animal wasimmediately placed back to the holding cage and after a 10-min intervalthe 2^(nd) rectal temperature (T2) was taken using the same procedure asin measuring T1. Before each insertion, the rectal probe was cleanedwith an alcohol pad and lubricated with sterile K—Y jelly.

Chlordiazepoxide (10 mg/kg) was used as the positive control. Compoundsof the present invention, vehicle (45% hydroxypropyl beta-cyclodextrin)and chlordiazepoxide were administered orally to all groups (n=10 miceper group) 60 minutes prior to behavioral testing. All data wereanalyzed using an analysis of variance (ANOVA) followed by Fisher's PLSDpost hoc test. An effect was considered significance if p<0.05.Statistical outliers above or below 2 standard deviations from the meanin any of the temperature measures were removed from the final analysis.Results are displayed in Table 5. The results showed that followingadministration of compounds of the present invention, the SIH responsewas significantly smaller than when vehicle alone was administered. Thedata indicate that when the compounds of the present invention areadministered, the stress response is significantly reduced.

TABLE 5 Effects of compounds in the mouse SIH test Treatment Change inTemperature (T2 − T1) ° C. Dose (mg/kg, PO) Mean ± S.E.M. 72 0 0.69 ±0.07 3  0.21 ± 0.11* 10  0.32 ± 0.05* 30 0.44 ± 0.10 Chlordiazepoxide 10−0.25 ± 0.15* 200 0 0.74 ± 0.09 3 −0.13 ± 0.11* 10 −0.50 ± 0.15* 30−0.66 ± 0.13* Chlordiazepoxide 10 −0.66 ± 0.10* 211 0 0.79 ± 0.09 3 0.37 ± 0.08* 10  0.33 ± 0.09* 30  0.37 ± 0.09* Chlordiazepoxide 10−0.37 ± 0.09* 32 0 0.60 ± 0.05 3  0.26 ± 0.04* 10  0.28 ± 0.10* 30  0.37± 0.06* Chlordiazepoxide 10  −0.2 ± 0.07* 77 0 0.70 ± 0.10 3 0.37 ± 0.1510 0.55 ± 0.11 30 0.55 ± 0.12 Chlordiazepoxide 10 −0.56 ± 0.23* *p value< 0.05

Example 248

Conflict Protocol:

The conflict procedure is a well established operant conditioningapproach to evaluate anxiolytic-like effects of test compounds. In thisprocedure, positively-reinforced behavior is suppressed byresponse-contingent administration of a noxious stimulus (i.e., mildelectric shock). Compounds with anxiolytic effects in humans (e.g.,benzodiazepines) characteristically increase rates of responding thatare suppressed by shock and are referred to as anti-conflict oranxiolytic-like effects. The conflict procedure has good predictivevalidity and positive correlations between the potency ofbenzodiazepines to produce anti-conflict effects and clinical efficacyhave been demonstrated (Cook and Davidson, 1973; Kleven and Koek, 1999;Rowlett et al. 2006). In addition to anxiolytic-like effects, conflictprocedures also provide an assessment of the ability of the animal toperform operant lever pressing. This is typically assessed by includinglever pressing in the absence of the noxious stimulus. Most anxiolyticcompounds will decrease rates of responding in the absence of shock atdoses higher than those that induce anxiolytic-like effects. The effectscontributing to anxiolytic-induced decreases in non-suppressedresponding are not well understood, but likely consist of a combinationof motor co-ordination deficits and sedative effects.

Adult rhesus monkeys were used in these studies (n=1-4). Weights of themonkeys ranged from 6.2 to 10.5 kg. The animals had been previouslytrained using the conflict procedure. Animals were maintained at 85-95%of their free-feeding weights by manipulation of food intake. Monkeyswere individually housed with water available ad libitum, and maintainedon a 12 hour lights-on/12 hour lights-off cycle (lights on at 0600a.m.). Monkeys received Harlan Teklad diet (15% Primate Diet) as well assupplemental feeding (fruits, vegetables, and commercially availableprimate treats) daily. They were also given toys and video enrichmentwhen not in an experimental session. Each animal was prepared prior tothe study with a chronic indwelling venous catheter for drug delivery. Apolyvinyl chloride catheter was implanted in a jugular, femoral orbrachial vein under isoflurane anesthesia and aseptic conditions. Theproximal end of the catheter terminated above the right atrium, and thedistal end was passed subcutaneously to exit in the midscapular region.Experimental sessions began 5-7 days following surgery. Catheters hadbeen implanted approximately 3 months to 1 year prior to the initiationof the study. During experimental sessions, monkeys were seated inprimate chairs that were placed in ventilated sound-attenuatingchambers. A single response lever was mounted on the wall of the chamberin front of the monkey. Each press of a lever produced an audible clickand was recorded as a response via electromechanical equipment, acomputer interface, and PC with specialized software. Food pellets couldbe delivered into a tray located next to the lever. Mild electric shockcould be delivered to the bottom of the feet via brass electrodes thatwere fitted to shoes. Red and green lights mounted above the leverscould be illuminated to serve as visual stimuli.

Monkeys were trained under a multiple schedule of food reinforcementadapted from Spealman (1979). A daily session consisted of 4 cycles,each preceded by a 10-min time out period in which all lights in thechamber were off and responding had no programmed consequences. Eachcycle consisted of two components, component 1 and 2. Component 1 wassignaled by red stimulus lights and consisted of an 18-response schedule(FR18) of food pellet delivery (i.e., the animal receives a food pelletfollowing 18 responses). Component 2, signaled by green stimulus lights,followed immediately and consisted of the FR18 schedule of food deliverycombined with a FR20 schedule of foot shock delivery (1.5-3.0 mA,adjusted for each monkey based on individual performance, 0.25 secduration). Delivery of a food pellet (FR18 schedule) was followed by a10 sec time out in which responses had no programmed consequences. Bothcomponents were 5 min in duration, or ended after the monkey obtained 5food pellets or received 3 foot shocks, whichever occurred first.

Sessions were conducted 5 days per week at approximately the same timeeach day. During training sessions, monkeys received i.v. injections ofsaline (0.1 ml/kg) in the 5^(th) minute of each 10-min time out. Forindividual monkeys, performance was considered stable if the averagerates of responding (responses/second) for component 1 and component 2did not vary by ±20% over five consecutive sessions, with no upward ordownward trends. Test sessions were initiated once performance wasstable, and continued as long as the stability criteria were met oninterceding training sessions. No training or test sessions wereconducted the day after a test session.

During test sessions (conducted once or twice per week), i.v. injectionsof vehicle or compound were administered in the 5^(th) minute of eachtime out. Volume of vehicle matched the highest concentration ofcompound administered (˜0.5 ml/kg) and as described above, differentvolumes of compound were administered followed by a 2 ml injection ofsaline. In successive cycles, increasing doses of the test compound wereadministered using a cumulative dosing procedure, in which the dose ofcompound was increased in ½ log₁₀ units.

Data were expressed as the mean number of responses/second (±S.E.M.).All data were analyzed using a repeated measures analysis of variance(ANOVA) followed by Fisher's PLSD post hoc test. An effect wasconsidered significance if p<0.05. The results are displayed in Table 6.

TABLE 6 Effects of exemplary compounds in the rhesus monkey conflicttest Non-Suppressed Suppressed Response Rates Response Rates Treatment(Responses/Second) (Responses/Second) Dose (mg/kg, IV) Mean ± S.E.M.Mean ± S.E.M. Alprazolam 0 2.55 ± 0.27 0.02 ± 0.01 0.003 2.18 ± 0.260.04 ± 0.02 0.01 2.62 ± 0.32 0.76 ± 0.26 0.03 2.38 ± 0.36  2.28 ± 0.55*0.1  1.16 ± 0.26*  1.44 ± 0.57* 200 0.3 3.2 0.02 1 2.9 0.02 1.8 2.4 1.4*3 3.1 1.2* 5.6 3.3 1.9* 105 0 2.62 ± 0.36 0.06 ± 0.04 0.1 2.68 ± 0.370.02 ± 0.01 0.3 2.68 ± 0.39 0.47 ± 0.44 1 2.78 ± 0.36 0.79 ± 0.45 3 1.02 ± 0.57* 0.46 ± 0.32 32 0 2.38 ± 0.37 0.02 ± 0.01 0.1 2.50 ± 0.290.03 ± 0.01 0.3 2.58 ± 0.44 0.24 ± 0.17 1 1.82 ± 0.67  1.1 ± 0.67 3 1.77± 0.64  1.19 ± 0.36* *p value < 0.05

Example 248

Four Plate Test (FPT) Protocol:

The four plate test (FPT) is an animal model of anxiety in which simpleongoing behavior (exploration of novel surroundings) is suppressed bythe delivery of mild electric foot-shock contingent to quadrant crossing(Aron, et al., 1971). Clinically effective classes of anxiolyticcompounds such as benzodiazepines, selective serotonin reuptakeinhibitors, or 5-HT_(1A) receptor agonists produce a markedanti-punishment effect (an increase in punished crossings), which isthought to indicate anxiolytic activity (Aron, et al., 1971; Bourin, etal., 1992; Hascoet, et al., 2000; Ring, et al., 2006). The four plateapparatus (Bioseb, Chaville France) consists of a cage (18×25×16 cm)floored by four identical rectangular metal plates (8×11 cm) separatedfrom one another by a gap of 4 mm. The plates are connected to a shockerunit that can generate electric foot shocks.

Male Swiss Webster (CFW) mice from Charles River (Wilmington, Mass.)were used for the FPT. Mice were received at 3-weeks of age. Uponreceipt, mice were assigned unique identification numbers (tail marked)and were group housed with 4 mice per cage in mouse ventilated racks.All animals remained housed in groups of four during the remainder ofthe study. All mice were acclimated to the colony room for at least oneweek prior to testing and were subsequently tested at an average age of4 weeks of age. During the period of acclimation, mice and rats wereexamined on a regular basis, handled, and weighed to assure adequatehealtH, D and suitability. Animals were maintained on a 12/12 light/darkcycle. The room temperature was maintained between 20 and 23° C. with arelative humidity maintained between 30% and 70%. Chow and water wereprovided ad libitum for the duration of the study. In each test, animalswere randomly assigned across treatment groups. Alprazolam (0.3 mg/kg)was used as the positive control. Compounds of the present invention,vehicle (45% hydroxypropyl beta-cyclodextrin) and alprazolam wereadministered orally to all groups (n=10 mice per group) 30 minutes priorto behavioral testing. Following pretreatment, mice were gently placedin the four plate chamber and allowed to explore the enclosure for 18seconds. After the exploration period, every time the mouse crossed fromone plate to another, the experimenter, blind to the dosing conditions,administered a mild electric foot-shock, and referred to as a punishedcrossing. The intensity and duration of the foot-shock were 0.5 mA for0.5 seconds. The number of punished crossings was recorded during the 2min test session. The plates were thoroughly cleaned with 70% ethanolimmediately after each mouse. All data were analyzed using an analysisof variance (ANOVA) followed by Fisher's PLSD post hoc test. An effectwas considered significance if p<0.05. Statistical outliers above orbelow 2 standard deviations from the mean in any of the temperaturemeasures were removed from the final analysis. Results are displayed inTable 7.

TABLE 7 Effects of compounds in the mouse four plate test TreatmentNumber of Punished Crossings Dose (mg/kg, PO) Mean ± S.E.M. 211 0 4.9 ±0.23 3  7.8 ± 0.59* 10  8.6 ± 0.85* 30  8.9 ± 0.57* Alprazolam 0.3 12.5± 1.17* 76 0 4.8 ± 0.25 3  6.7 ± 0.45* 10  6.9 ± 0.35* 30  6.3 ± 0.62*Alprazolam 0.3 11.9 ± 0.46* 60 0 6.2 ± 0.36 3 6.3 ± 0.45 10 6.3 ± 0.7030 6.0 ± 0.30 Alprazolam 0.3 11.6 ± 0.65* 72 0 4.9 ± 0.46 3 5.8 ± 0.6310 5.2 ± 0.47 30 4.8 ± 0.36 Alprazolam 0.3 12.1 ± 0.94* 200 0 5.8 ± 0.293  7.2 ± 0.52* 10  8.6 ± 0.43* 30  7.5 ± 0.39* Alprazolam 0.3 12.4 ±0.42* 77 0 4.8 ± 0.20 3 4.3 ± 0.26 10 4.6 ± 0.31 30 5.0 ± 0.37Alprazolam 0.3  9.6 ± 0.65* 32 0 5.7 ± 0.94 3 6.6 ± 0.72 10 6.6 ± 0.6730 5.7 + 0.94 Alprazolam 0.3 12.0 ± 0.58* 105 0 5.4 ± 0.22 3 6.7 ± 0.3410 5.5 ± 0.60 30 5.6 ± 0.52 Alprazolam 0.3  9.4 ± 0.41* *p value < 0.05

Example 249

Vogel Conflict Test Protocol:

The Vogel conflict test is an animal model of anxiety described by Vogelet al. (1971). In this test, water deprived animals are placed in a cagewith free access to a drinking bottle. Whenever the animal drinks, anelectric shock is administered. Animals punished during drinking rapidlycease to drink. Anxiolytic drugs decrease the effect of punishment andincrease the number of shocks accepted by the rats in this conflictsituation. Male Wistar rats were used in these studies. Rats weredeprived of water for approximately 48 hours and then placedindividually into a transparent Plexiglas enclosure with a floorconsisting of stainless steel bars spaced 1 cm apart. The back wall ofthe enclosure was made of opaque Plexiglas thereby concealing theobserver from the experimental animal. In the center of the oppositewall, 5 cm above the floor, a metal water spout protruded into the cageand was connected to one pole of a shock generator. The other pole ofthe shock generator was connected to the metal grid floor. The rat isleft to explore until it finds the water spout. Then, every time itdrinks, it receives an electric shock (1.7 mA, 1 sec duration) 2 secondsafter it starts drinking. The number of punished drinks is countedduring a 3 minute test. Ten rats are studied per treatment group.Clobazam (64 mg/kg) was used as the positive control. Compounds of thepresent invention, vehicle (45% hydroxypropyl beta-cyclodextrin) andclobazam were administered orally to all groups (n=10 mice per group) 60minutes prior to behavioral testing. All data were analyzed usingunpaired Student's t-tests. An effect was considered significance ifp<0.05. Results are displayed in Table 8.

TABLE 8 Effects of compounds in the rat Vogel conflict test TreatmentNumber of Shocks Dose (mg/kg, PO) Mean ± S.E.M. 32 0 4.2 ± 0.5 3 3.8 ±0.6 10 3.8 ± 0.7 30 6.6 ± 2.3 Clobazam 64  8.3 ± 1.2* 105 0 5.3 ± 1.1 35.1 ± 0.6 10 5.8 ± 0.8 30 8.2 ± 1.8 Clobazam 64 10.1 ± 1.2* 211 0 5.2 ±0.8 3 3.9 ± 0.5 10 5.3 ± 0.8 30 5.0 ± 1.1 Clobazam 64  8.9 ± 0.8* 200 04.0 ± 0.5 3 8.4 ± 2.1 10  8.9 ± 2.3* 30  9.5 ± 2.1* Clobazam 64  9.2 ±0.7* 40 0 3.0 ± 0.4 1 2.4 ± 0.4 3 3.4 ± 0.7 10 4.4 ± 0.7 Clobazam 64 6.6 ± 1.0* 170 0 4.6 ± 0.6 0.3 5.1 ± 0.9 1 5.6 ± 0.9 3 6.5 ± 1.0Clobazam 64  8.4 ± 1.3* *p value < 0.05

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference for allpurposes.

1. A compound having the structure:

wherein: R¹, R², R³ and R⁴ are each members independently selected fromH, D, halogen, hydroxyl, dialkylamino, cyano, sulfonamide, acyl,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl, whereina member selected from R¹ and R³, R² and R⁴ and a combination thereofare optionally joined in a ring; R⁵ and R⁶ are each a memberindependently selected from H, D, F, hydroxyl, substituted orunsubstituted alkoxy and lower alkyl, wherein R⁵ and R⁶ are optionallyjoined into a ring; Q is a member selected from:

wherein ring A¹ is an unsubstituted 4, 6 or 7 member monocyclic, asubstituted 4, 5, 6 or 7 member monocyclic or an optionally substituted8, 9, 10, 11 or 12 member bicyclic ring comprising 0, 1, 2, 3 or 4heteroatoms independently selected from N, O and S; ring A² is asubstituted 4, 5, 6 or 7 member monocyclic or an optionally substituted8, 9, 10, 11 or 12 member bicyclic ring comprising 0, 1, 2, 3 or 4heteroatoms independently selected from N, O and S; ring A³ is chosenfrom substituted or unsubstituted thiadiazolyl, substituted orunsubstituted pyridazinyl, substituted or unsubstituted oxadiazolyl,substituted or unsubstituted triazinyl, substituted or unsubstitutedpyrazolyl, substituted or unsubstituted pyrimidinyl, substituted orunsubstituted triazolyl, substituted or unsubstituted indolinyl,substituted or unsubstituted furopyrrolyl, substituted or unsubstitutedindolyl, substituted or unsubstituted isoindolyl, substituted orunsubstituted benzotriazolyl, substituted or unsubstitutedbenzooxazolyl, substituted or unsubstituted pyridinyl, substituted orunsubstituted tetrazolyl, substituted or unsubstituted thiazolyl,substituted or unsubstituted thiadiazolyl, substituted or unsubstitutedindazolyl, substituted or unsubstituted pyrazinyl, substituted orunsubstituted benzooxazinyl, substituted or unsubstituted oxazolyl,substituted or unsubstituted benzyl, substituted or unsubstitutedphenyl, substituted or unsubstituted benzothiadiazonyl, substituted orunsubstituted thiopheneyl, substituted or unsubstituted quinolinyl,substituted or unsubstituted quinazolinyl, substituted or unsubstitutedoxazolidinyl and substituted or unsubstituted azetidinyl; X is selectedfrom O, S and NR⁷, wherein R⁷ is selected from H, D, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl; Y is a member selected from a bond,(CR⁸R⁹)_(n), O, S, NR¹⁰R¹¹, S(O), S(O)₂, S(O)pNR¹⁰R¹¹,(CR⁸R⁹)_(n)G(CR⁸R⁹)_(m) wherein G is a member selected from a bond andO; m and n are independently selected integers from 0 to 4; each R⁸, R⁹and R¹⁰ are independently selected from H, D, substituted orunsubstituted alkyl, acyl, SO₂R^(8a), OR^(8a), COOR^(8a), andCONR^(8a)R^(8b), wherein R^(8a) and R^(8b) are independently selectedfrom H, D, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl, whereina member selected from R⁸ and R⁹, R^(8a) and R^(8b) and a combinationthereof are optionally joined in a ring; R¹¹ is selected from a bond andNR^(11a) wherein R^(11a) is selected from H, D, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl; and Z is.
 2. The compound of claim 1, whereinR⁵ and R⁶ are both H.
 3. The compound of claim 1, wherein Q is

and ring A¹ is selected from substituted or unsubstituted heteroaryl. 4.(canceled)
 5. The compound of claim 3 wherein ring A¹ is a memberselected from:


6. The compound of claim 1 wherein Q is


7. The compound of claim 6 wherein Q is a member selected from:


8. The compound of claim 1 wherein Q is


9. The compound of claim 8 wherein Q is a member selected from:


10. The compound of claim 1 wherein A¹, A² or A³ is selected fromsubstituted or unsubstituted thiadiazolyl, substituted or unsubstitutedpyridazinyl, substituted or unsubstituted oxadiazolyl, substituted orunsubstituted triazinyl, substituted or unsubstituted pyrazolyl,substituted or unsubstituted pyrimidinyl, substituted or unsubstitutedtriazolyl, substituted or unsubstituted benzoimidazolyl, substituted orunsubstituted indolinyl, substituted or unsubstituted furopyrrolyl,substituted or unsubstituted indolyl, substituted or unsubstitutedbenzotriazolyl, substituted or unsubstituted benzooxazolyl, substitutedor unsubstituted pyridinyl, substituted or unsubstituted tetrazolyl,substituted or unsubstituted thiazolyl, substituted or unsubstitutedindazolyl, substituted or unsubstituted diazolyl, substituted orunsubstituted purinyl, substituted or unsubstituted pyrazinyl,substituted or unsubstituted imidazopyridinyl, substituted orunsubstituted benzooxazinyl, substituted or unsubstituted oxazolyl,substituted or unsubstituted benzyl, substituted or unsubstitutedbenzothiadiazonyl, substituted or unsubstituted thiopheneyl, substitutedor unsubstituted quinolinyl, substituted or unsubstituted quinazolinyl,substituted or unsubstituted oxazolidinyl, substituted or unsubstitutedimidazolidinyl and substituted or unsubstituted azetidinyl. 11.-16.(canceled)
 17. A compound having a structure selected from:

wherein R¹⁶ and R¹⁷ are independently selected from H, D, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl and NR¹⁸R¹⁹ wherein R¹⁸ and R¹⁹ are substituted orunsubstituted alkyl, and R¹⁸ and R¹⁹ are optionally joined in a ring; ais an integer selected from 1, 2 and 3; and Q is selected fromsubstituted or unsubstituted heterocycloalkyl and substituted orunsubstituted heteroaryl
 18. The compound of claim 17 wherein Q has thestructure:—R²⁰-R²¹ wherein R²⁰ is selected from a bond and NH; and R²¹ is selectedfrom substituted or unsubstituted heterocycloalkyl and substituted orunsubstituted heteroaryl
 19. The compound of claim 18 wherein Q has astructure selected from:

20.-50. (canceled)
 51. The compound according to claim 1 as apharmaceutically acceptable salt.
 52. A pharmaceutical compositioncomprising a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 53. A method for treating or preventing a disease orcondition selected from the group consisting of anxiety disorders,psychiatric disorders, convulsive disorders, aggressive behavior, musclespasms or tension, depressive or bipolar disorders, cognitive disorders,sleeping disorders, neurodegenerative eye diseases, neurodegeneration,pain, schizophrenia, emesis and eating disorders, comprisingadministering to a patient a therapeutically effective amount of thecomposition of claim
 52. 54. A method for modulating GABA_(A) receptorsubtypes comprising administering to a patient a therapeuticallyeffective amount of a compound according to the composition of claim 52.55. A method for inhibiting a benzodiazepine receptor comprisingadministering to a patient a therapeutically effective amount of acompound according to claim 1.